Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors

ABSTRACT

Substituted heteroaromatic compounds, and in particular substituted bicyclic heteroaromatic compounds of formula (I), wherein X is N or CH; A represents a fused 5, 6 or 7-membered heterocyclic ring containing 1 to 5 heteroatoms which may be the same or different and which are selected from N, O or S(O) m , wherein m is as defined above, the heterocyclic ring containing a total of 1, 2 or 3 double bonds inclusive of the bond in the pyridine or pyrimidine ring to which it is fused, with the provisos that the heterocyclic ring does not form part of a purine and that the fused heterocyclic ring does not contain two adjacent O or S(O) m  atoms. U represents a 5 to 10-membered mono or bicyclic ring system in which one or more of the carbon atoms is optionally replaced by a heteroatom independently selected from N, O and S(O) m , wherein m is 0, 1 or 2 and wherein the ring system is substituted by at least one independently selected R 6  group and is optionally substituted by at least one independently selected R 4  group, with the proviso that U does not represent phenyl; are protein tyrosine kinase inhibitors. The compounds are described as are methods for their preparation, pharmaceutical compositions including such compounds and their use in medicine, for example in the treatment of cancer and psoriasis.

This application is a 371 of PCT/EP97/03674, filed Jul. 11, 1997.

The present invention relates to a series of substituted heteroaromaticcompounds, methods for their preparation, pharmaceutical compositionscontaining them and their use in medicine. In particular, the inventionrelates to bioisosteres of quinoline and quinazoline derivatives whichexhibit protein tyrosine kinase inhibition.

Protein tyrosine kinases catalyse the phosphorylation of specifictyrosyl residues in various proteins involved in the regulation of cellgrowth and differentiation (A. F. Wilks, Progress in Growth FactorResearch, 1990, 2, 97-111; S. A. Courtneidge, Dev. Supp.l, 1993, 57-64;J. A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R. F. Paulson,Semin. Immunol., 1995, 7(4), 267-277; A. C. Chan, Curr. Opin. Immunol.,1996, 8(3), 394-401). Protein tyrosine kinases can be broadly classifiedas receptor (e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) ornon-receptor (e.g. c-src, lck, Zap70) kinases. Inappropriate oruncontrolled activation of many of these kinase, i.e. aberrant proteintyrosine kinase activity, for example by over-expression or mutation,has been shown to result in uncontrolled cell growth.

Aberrant activity of protein tyrosine kinases, such as c-erbB-2, c-src,c-met, EGFr and PDGFr have been implicated in human malignancies.Elevated EGFr activity has, for example, been implicated in non-smallcell lung, bladder and head and neck cancers, and increased c-erbB-2activity in breast, ovarian, gastric and pancreatic cancers. Inhibitionof protein tyrosine kinases should therefore provide a treatment fortumours such as those outlined above.

Aberrant protein tyrosine kinase activity has also been implicated in avariety of other disorders: psoriasis, (Dvir et al, J. Cell. Biol; 991,113, 857-865), fibrosis, atherosclerosis, restenosis, (Buchdunger et al,Proc. Natl. Acad. Sci. USA; 1991, 92, 2258-2262), auto-immune disease,allergy, asthma, transplantation rejection (Klausner and Samelson, Cell;1991, 64, 875-878), inflammation (Berkois, Blood; 1992, 79(9),2446-2454), thrombosis (Salari et al, FEBS; 1990, 263(1), 104-108) andnervous system diseases (Ohmichi et al, Biochemistry, 1992, 31,4034-4939). Inhibitors of the specific protein tyrosine kinases involvedin these diseases eg PDGF-R in restenosis and EGF-R in psoriasis, shouldlead to novel therapies for such disorders. P56lck and zap 70 areindicated in disease conditions in which T cells are hyperactive e.g.rheumatoid arthritis, autoimmune disease, allergy, asthma and graftrejection. The process of angiogenesis has been associated with a numberof disease states (e.g. tumourogenesis, psoriasis, rheumatoid arthritis)and this has been shown to be controlled through the action of a numberof receptor tyrosine kinases (L. K. Shawver, DDT, 1997, 2(2), 50-63).

EP0635507 discloses a class of tricyclic quinazoline derivatives of theformula:

wherein R¹ and R² together form specified optionally substituted groupscontaining at least one heteroatom so as to form a 5 or 6-membered ring,in which there is a N atom at the 6 position of the quinazoline ring; R³includes independently hydrogen, hydroxy, halogeno, (1-4C)alkyl, (1-4C)alkoxy di-[(1-4C)alkyl]amino, or (2-4C)alkanoylamino. The above citationnotes that receptor tyrosine kinases in general, which are important inthe transmission of biochemical signals initiating cell replication, arefrequently present at increased levels or with higher activities incommon human cancers such as breast cancer (Sainsbury et al, Brit, J.Cancer, 1988, 58, 458). It is suggested that inhibitors of receptortyrosine kinase should be of value as inhibitors of the growth ofmammalian cancer cells (Yaish et al. Science, 1988, 242, 933). Thiscitation therefore has the aim of providing quinazoline derivativeswhich inhibit receptor tyrosine kinases involved in controlling thetumourigenic phenotype.

WO 95/15758 discloses aryl and heteroaryl quinazoline derivatives offormula

wherein X includes a bond, O, S, SO, SO₂, C≡C, C═C, CH₂ and NH; Arincludes phenyl, naphthyl, naphthalenyl, indolyl, pyridyl, piperidinyl,piperazinyl, dinydroquinolinyl, tetrahydroquinolinyl, thienyl, indanyl,pyrazolyl and 1,4-benzodioxanyl; and R₅, R₆ and R₇ independently includehydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl,halo, haloalkyl, carboxy or carbalkoxy; as inhibitors of CSF-1R and/orp56lck receptor tyrosine kinase activity.

WO 95/19774 discloses bicyclic derivatives of formula:

in which A to E are nitrogen or carbon and at least one of A to E isnitrogen; or two adjacent atoms together are N, O or S; R₁ is H or alkyland n is 0, 1 or 2; m is 0 to 3 and R₂ includes optionally substitutedalkyl, alkoxy, cycloalkoxy, cycloalkoxy, or two R₂ groups together forma carbocycle or heterocycle. The compounds are said to inhibit epidermalgrowth factor receptor tyrosine kinase and suggested uses include thetreatment of cancer, psoriasis, kidney disease, pancreatitis andcontraception.

WO 96/07657 discloses pyrimido[5,4-d]pyrimidine derivatives of formula

wherein Ra includes hydrogen or alkyl; Rb includes optionallysubstituted phenyl; and Rc includes hydrogen, halo, alkyl, cycloalyl,cycloalkylalkylanyl, aralkyl, OH, optionally substituted alkoxy,cycloalkoxy, aryloxy, aralkoxy, mercapto, optionally substituted alkyl-or arysulfenyl, -sulfinyl, or -sulfonyl and substituted alkyleneimino;as EGF-R inhibitors.

WO 96/09294 discloses quinoline and quinazoline derivatives of formula

wherein X is N or CH; Y includes O, S, CH₂O and NH; R⁶ includes phenoxy,benzylozy, benzylmercapto, benzylamino, benzyl, anilino, benzoyl,anilinocarbonyl, anilnomethyl, phenylethynyl, phenylethenyl,phenylethyl, phenylthio, phenylsulphonyl, benzylthio, benzylsulphonyl,phenylthiomethyl, phenylsulphonylmethyl, phenoxymethyl, thienylmethoxy,furanylmethoxy, cyclohexyl, and cyclohexylmethoxy; and R¹, R², R³ andR^(3′) include a range of possible substituents, predominantly notincluding heterocyclic ring systems; as protein receptor tyrosine kinaseinhibitors, in particular as c-erbB-2 and/or p56lck inhibitors.

WO 96/15118 discloses quinazoline derivatives of formula

wherein X includes O, S, SO, SO₂, CH_(2, OCH) ₂, CH₂O and CO; Q includesa phenyl or naphthyl group and various 5- or 6-membered heteroarylmoieties; n is 0, 1, 2 or 3

and each R² is independently halogeno, trifluoromethyl, hydroxy, amino,nitro, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, diC₁₋₄ alkylamino or C₂₋₄ alkanoylamino; m is 1, 2 or 3 and R¹ includes a range ofpossible substituents, predominantly not including heterocyclic ringsystems; as receptor tyrosine kinase inhibitors, in particular as EGF-Rinhibitors.

WO 96/15128 discloses pyrido[2,3-d]pyrimidine and naphthyridinederivatives of formula

wherein X is CH or N; B is halo, hydroxy or NR₃R₄; Ar includesunsubstituted and substituted phenyl or pyridyl; and R₁, R₂, R₃ and R₄independently include hydrogen, amino, C₁₋₈alkylamino,di-C₁₋₈alkylamino, unsubstituted and substituted aromatic orheteroaromatic groups, and unsubstituted and substituted C₁₋₈alkyl,C₂₋₈alkenyl or C₂₋₈alkynyl groups.

WO 96/16960 discloses quinazoline derivatives of formula

wherein m is 1 or 2; each R¹ independently includes hydrogen andC₁₋₄alkoxy; n is 1, 2 or 3; each R² independently includes hydrogen,halogeno and C₁₋₄alkyl, or R² is an aryl- or heteroaryl-containinggroup, including pyridylmethoxy and benzoyl; and Ar includes asubstituted or unsubstituted 5- or 9-membered nitrogen-linked heteroarylmoiety containing up to four nitrogen atoms, in particularimidazol-1-yl, imidazolin-1-yl, benzimidazol-1-yl, pyrazol-1-yl and1,2,4-triazol-1-yl; as receptor tyrosine kinase inhibitors, inparticular as EGF-R inhibitors.

It is therefore a general object of the present invention to providecompounds suitable for the treatment of disorders mediated by proteintyrosine kinase activity, and in particular treatment of the abovementioned disorders.

In addition to the treatment of tumours, the present invention envisagesthat other disorders mediated by protein tyrosine kinase activity may betreated effectively by inhibition, including preferential inhibition, ofthe appropriate protein tyrosine kinase activity.

Broad spectrum inhibition of protein tyrosine kinase may not alwaysprovide optimal treatment of, or example tumours, and could in certaincases even be detrimental to subjects since protein tyrosine kinasesprovide an essential role in the normal regulation of cell growth.

It is another object of the present invention to provide compounds whichpreferentially inhibit protein tyrosine kinases, such as EGFr, c-erbB-2,c-erbB-4, c-met, tie-2, PDGFr, c-src, lck, Zap70, and fyn. There is alsoperceived to be a benefit in the preferential inhibition involving smallgroups of protein tyrosine kinases, for example c-erbB-2 and c-erbB-4 orc-erbB-2, c-erbB-4 and EGF-R.

A further object of the present invention is to provide compounds usefulin the treatment of protein tyrosine kinase related diseases whichminimise undesirable side-effects in nthe recipient.

The present invention relates to heterocyclic compounds which may beused to treat disorders mediated by protein tyrosine kinases and inparticular have anti-cancer properties. More particularly, the compoundsof the present invention are potent inhibitors of protein tyrosinekinases such as such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr,c-src, lck, Zap70, and fyn, thereby allowing clinical management ofparticular diseasesd tissues.

The present invention envisages, in particular, the treatment of humanmalignancies, for example breast, non-small cell lung, ovary, stomach,and pancreatic tumours, especially those driven by EGFr or erbB-2, usingthe compounds of the present invention. For example, the inventionincludes compounds which are highly active against the c-erbB-2 proteintyrosine kinase often in preference to the EGF receptor kinase henceallowing treatment of c-erbB-2 driven tumours. However, the inventionalso includes compounds which are highly active against both c-erbB-2and EGF-R receptor kinases hence allowing treatment of a broader rangeof tumours.

More particularly, the present invention envisages that disordersmediated by protein tyrosine kinase activity may be treated effectivelyby inhibition of the appropriate protein tyrosine kinase activity in arelatively selective manner, thereby minimising potential side effects.

Accordingly, the present invention provides a compound of formula (I):

or a salt thereof;

wherein X is N or CH;

Y is a group W(CH₂), (CH₂)W, or W, in which W is O, S(O)_(m) wherein mis 0, 1 or 2, or NR^(a) wherein R^(a) is hydrogen or a C₁₋₈ aklyl group;

R″ represents a phenyl group or a 5- or 6-membered heterocyclic ringcontaining 1 to 4 heteroatoms selected from N, O or S(O)_(m), wherein mis as defined above, with the proviso that the ring does not contain twoadjacent O or S(O)_(m) atoms, the phenyl group or the heterocyclic ringbeing optionally substituted by one or more R¹ groups; and n=0 or 1;

each R¹ is independently selected from the group comprising amino,hydrogen, halogen, hydroxy, nitro, carboxy, formyl, cyano,trifluoromethyl, trifluoromethoxy, carbamoyl, ureido, guanidino, C₁₋₈alkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkoxy, C₄₋₈ alkylcycloalkoxy, C₁₋₈alkylcarbonyl, C₁₋₈ alkoxycarbonyl, N-C₁₋₄ alkylcarbamoyl, N,N-di-[C₁₋₄alkyl]carbamoyl, hydroxyamino, C₁₋₄ alkoxyamino, C₂₋₄ alkanoyloxyamino,C₁₋₄ alkylamino, di[C₁₋₄ alkyl]amino, di-[C₁₋₄ alkyl]amino-C₁₋₄alkylene-(C₁₋₄ alkyl)amino, C₁₋₄ alkylamino-C₁₋₄ alkylene-(C₁₋₄alkyl)amino, hydroxy-C₁₋₄ alkylene-(C₁₋₄ akyl)amino, phenyl, phenoxy,4-pyridon-1-yl, pyrrolidin-1-yl, imidazol-1-yl, piperidino, morpholino,thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,piperazin-1-yl, 4-C₁₋₄ alkylpiperazin-1-yl, dioxolanyl, C₁₋₈ alkylthio,arylthio, C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl, arylsulphinyl,arylsulphonyl, halogeno-C₁₋₄ alkyl, hydroxy-C₁₋₄ alkyl, C₂₋₄alkanoyloxy-C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, carboxy-C₁₋₄ alkyl,formyl-C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl-C₁₋₄-alkyl, carbamoyl-C₁₋₄ alkyl,N-C₁₋₄ alkylcarbamoyl-C₁₋₄alkyl, N,N-di-[C₁₋₄ alkyl]carbamoyl-C₁₋₄alkyl,amino-C₁₋₄ alkyl, C₁₋₄ alkylamino-C₁₋₄ alkyl, di-[C₁₋₄ alkyl]amino-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-pyridon-1-yl-C₁₋₄ alkyl,pyrrolidin-1-yl-C₁₋₄ alkyl, imidazol-1-yl-C₁₋₄ alkyl, piperidino-C₁₋₄alkyl, morpholino-C₁₋₄ alkyl, thiomorpholino-C₁₋₄alkyl,thiomorpholino-1-oxide-C₁₋₄alkyl, thiomorpholino-1,1-dioxide-C₁₋₄alkyl,piperazin-1-yl-C₁₋₄alkyl, 4-C₁₋₄ alkylpiperazin-1-yl-C₁₋₄ alkyl,hydroxy-C₂₋₄ alkoxy-C₁₋₄ alkyl, C₁₋₄ alkoxy-C₂₋₄ alkoxy-C₁₋₄ alkyl,hydroxy-C₂₋₄ alkylamino-C₁₋₄ alkyl, C₁₋₄ alkoxy-C₂₋₄ alkylamino-C₁₋₄alkyl, C₁₋₄ alkylthio-C₁₋₄ alkyl, hydroxy-C₂₋₄ alkylthio-C₁₋₄ alkyl,C₁₋₄ alkoxy-C₂₋₄ alkylthio-C₁₋₄ alkyl, phenoxy-C₁₋₄ alkyl, anilino-C₁₋₄alkyl, phenylthio-C₁₋₄ alkyl, cyano-C₁₋₄ alkyl, halogeno-C₂₋₄ alkoxy,hydroxy-C₂₋₄ alkoxy, C₂₋₄ alkanoyloxy-C₂₋₄ alkoxy, C₁₋₄ alkoxy-C₂₋₄alkoxy, carboxy-C₁₋₄ alkoxy, formyl-C₁₋₄ alkoxy, C₁₋₄alkoxycarbonyl-C₁₋₄ alkoxy, carbamoyl-C₁₋₄ alkoxy, N-C₁₋₄alkylcarbamoyl-C₁₋₄ alkoxy, N,N-di-[C₁₋₄ alkyl]carbamoyl-C₁₋₄ alkoxy,amino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄ alkoxy, di-[C₁₋₄alkyl]amino-C₂₋₄ alkoxy, di-[C₁₋₄ alkyl-C₂₋₄ alkoxy]amino-C₂₋₄ alkoxy,C₂₋₄ alkanoyloxy, hydroxy-C₂₋₄ alkanoyloxy, C₁₋₄alkoxy-C₂₋₄ alkanoyloxy,phenyl-C₁₋₄ alkoxy, phenoxy-C₂₋₄ alkoxy, anilino-C₂₋₄ alkoxy,phenylthio-C₂₋₄ alkoxy, 4-pyridon-1-yl-C₂₋₄ alkoxy, piperidino-C₂₋₄alkoxy, pyrrolidin-1-yl-C₂₋₄ alkoxy, imidazol-1-yl-C₂₋₄ alkoxy,morpholino-C₂₋₄ alkoxy, thiomorpholino-C₂₋₄ alkoxy,thiomorpholino-1-oxide-C₂₋₄ alkoxy, thiomorpholino-1,1-dioxide-C₂₋₄alkoxy, piperazin-1-yl-C₂₋₄ alkoxy, 4-C₁₋₄ alkylpiperazin-1-yl-C₂₋₄alkoxy, halogeno-C₂₋₄ alkylamino, hydroxy-C₂₋₄ alkylamino, C₂₋₄alkanoyloxy-C₂₋₄ alkylamino, C₁₋₄ alkoxy-C₂₋₄ alkylamino, carboxy-C₁₋₄alkylamino, C₁₋₄ alkoxycarbonyl-C₁₋₄ alkylamino, carbamoyl-C₁₋₄alkylamino, N-C₁₋₄ alkylcarbamoyl-C₁₋₄ alkylamino, N,N-di-[C₁₋₄alkyl]carbamoyl-C₁₋₄ alkylamino, amino-C₂₋₄ alkylamino, C₁₋₄alkylamino-C₂₋₄ alkylamino, di-[C₁₋₄alkyl]amino-C₂₋₄ alkylamino,phenyl-C₁₋₄ alkylamino, phenoxy-C₂₋₄ alkylamino, anilino-C₂₋₄alkylamino, 4-pyridon-1-yl-C₂₋₄ alkylamino, pyrrolidin-1-yl-C₂₋₄alkylamino, imidazol-1-yl-C₂₋₄ alkylamino, piperidino-C₂₋₄ alkylamino,morpholino-C₂₋₄ alkylamino, thiomorpholino-C₂₋₄ alkylamino,thiomorpholino-1-oxide-C₂₋₄ alkylamino, thiomorpholino-1,1-dioxide-C₂₋₄alkylamino, piperazin-1-yl-C₂₋₄ alkylamino, 4-(C₁₋₄alkyl)piperazin-1-yl-C₂₋₄ alkylamino, phenylthio-C₂₋₄ alkylamino, C₂₋₄alkanoylamino, C₁₋₄ alkoxycarbonylamino, C₁₋₄ alkylsulphonylamino, C₁₋₄alkylsulphinylamino, benzamido, benzenesulphonamido, 3-phenylureido,2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halogeno-C₂₋₄alkanoylamino, hydroxy-C₂₋₄ alkanoylamino, hydroxy-C₂₋₄ alkanoyl-(C₁₋₄alkyl)amino, C₁₋₄ alkoxy-C₂₋₄ alkanoylamino, carboxy-C₂₋₄ alkanoylamino,C₁₋₄ alkoxycarbonyl-C₂₋₄ alkanoylamino, carbamoyl-C₂₋₄ alkanoylamino,N-C₁₋₄ alkylcarbamoyl-C₂₋₄ alkanoylamino, N,N-di-[C₁₋₄alkyl]carbamoyl-C₂₋₄ alkanoylamino, amino-C₂₋₄ alkanoylamino, C₁₋₄alkylamino-C₂₋₄ alkanoylamino or di-[C₁₋₄ alkyl]amino-C₂₋₄alkanoylamino, and wherein said benzamido or benzenesulphonamidosubstituent or any anilino, phenoxy or phenyl group on a R¹ substituentmay optionally bear one or two halogeno, C₁₋₄ alkyl or C₁₋₄ alkoxysubstituents; and wherein any substituent containing a heterocyclic ringmay optionally bear one or two halogeno, C₁₋₄ alkyl or C₁₋₄ alkoxysubstituents on said ring; and wherein any substituent containing aheterocyclic ring may optionally bear one or two oxo or thioxosubstituents on said ring;

or R¹ represents a group selected from M¹-M²-M³-M⁴, M¹-M⁵ orM¹-M²-M^(3′)-M⁶ wherein

M¹ represents a C₁₋₄ alkyl group, wherein optionally a CH₂ group isreplaced by a CO group;

M² represents NR¹² or CR¹²R¹³, in which R¹² and R¹³ each independentlyrepresent H or C₁₋₄ alkyl;

M³ represents a C₁₋₄ alkyl group;

M^(3′) represents a C₁₋₄ alkyl group or is absent;

M⁴ represents CN, NR¹²S(O)_(m)R¹³, S(O)_(m)NR¹⁴R¹⁵, CONR¹⁴R¹⁵,S(O)_(m)R¹³ or CO₂R¹³, in which R¹², R¹³ and m are as hereinbeforedefined and R¹⁴ and R¹⁵ each independently represent H or C₁₋₄ alkyl, orR¹⁴ and R¹⁵ together with the nitrogen atom to which they are attachedrepresent a 5- or 6-membered ring optionally containing 1 or 2additional heteroatoms selected from N, O or S(O)_(m) in which ring anynitrogen atom present may optionally be substituted with a C₁₋₄ alkylgroup, and which ring may optionally bear one or two oxo or thioxosubstituents;

M⁵ represents the group NR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are as definedabove, or M⁵ represents the group

in which t represents 2 to 4 and R¹⁶ represents OH, OC₁₋₄ alkyl orNR¹⁴R¹⁵; and

M⁶ represents a C₃₋₆ cycloalkyl group, the group NR¹⁴R¹⁵, wherein R¹⁴and R¹⁵ are as defined above, or a 5- or 6-membered heterocyclic ringsystem containing 1 to 4 heteroatoms selected from N, O or S;

and p is 0 to 3; or when p is 2 or 3, two adjacent R¹ groups togetherform an optionally substituted methylenedioxy or ethylenedioxy group;

R² is selected from the group comprising hydrogen, halogen,trifluoromethyl, C₁₋₄ alkyl and C₁₋₄ alkoxy;

U represents a 5 to 10-membered mono or bicyclic ring system in whichone or more of the carbon atoms is optionally replaced by a heteroatomindependently selected from N, O and S(O)_(m), wherein m is 0, 1 or 2and wherein the ring system is substituted by at least one independentlyselected R⁶ group and is optionally substituted by at least oneindependently selected R⁴ group, with the proviso that U does notrepresent phenyl;

each R⁴ is independently hydrogen, hydorxy, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylamino, di-[C₁₋₄ alkyl]amino, C₁₋₄ alkylthio, C₁₋₄alkylsulphinyl, C₁₋₄ alkylsulphonyl, C₁₋₄ alkylcarbonyl, C₁₋₄alkylcarbamoyl, di-[C₁₋₄ alkyl]carbamoyl, carbamyl, C₁₋₄ alkoxycarbonyl,cyano, nitro or trifluoromethyl;

each R⁶ is independently a group ZR⁷ wherein Z is joined to R⁷ through a(CH₂)p group in which p is 0, 1 or 2 and Z represents a group V(CH₂),V(CF₂), (CH₂)V, (CF₂)V, V(CRR′), V(CHR) or V where R and R′ are eachC₁₋₄ alkyl and in which V is a hydrocarby group containing 0,1 or 2carbon atoms, carbonyl, dicarbonyl, CH(OH), CH(CN), sulphonamide, amide,O, S(O)_(m) or NR^(b) where R^(b) is hydrogen or R^(b) is C₁₋₄ alkyl;and R⁷ is an optionally substituted C₃₀₆ cycloalkyl; or an optionallysubstituted 5, 6, 7, 8, 9 or 10-membered carbocyclic or heterocyclicmoiety;

or R⁶ is a group ZR⁷ in which Z is NR^(b), and NR^(b) and R⁷ togetherform an optionally substituted 5, 6, 7, 8, 9 or 10-membered carbocyclicor heterocyclic moiety;

A represents a fused 5, 6 or 7-membered heterocyclic ring containing 1to 5 heteroatoms which may be the same or different and which areselected from N, O or S(O)_(m), wherein m is as defined above, theheterocyclic ring containing a total of 1, 2 or 3 double bonds inclusiveof the bond in the pyridine or pyrimidine ring to which it is fused,with the provisos that the heterocyclic ring does not form part of apurine and that the fused heterocyclic ring does not contain twoadjacent O or S(O)_(m) atoms.

Solvates of the compounds of formula (I) are also included within thescope of the present invention.

Heterocyclic groups comprise one or more rings which may be saturated,unsaturated, or aromatic and which may independently contain one or moreheteroatoms in each ring.

Carbocyclic groups comprise one or more rings which may be independentlysaturated, unsaturated, or aromatic and which contain only carbon andhydrogen.

Suitably the 5, 6, 7, 8, 9 or 10-membered heterocyclic moiety isselected from the group comprising: furan, dioxolane, thiophene,pyrrole, imidazole, pyrrolidine, pyran, pyridine, pyrimidine,morpholine, piperidine, oxazole, isoxazole, oxazoline, oxazolidine,thiazole, isothiazole, thiadiazole, benzofuran, indole, isoindole,quinazoline, quinoline, isoquinoline and ketal.

Suitably the 5, 6, 7, 8, 9 or 10-membered carbocyclic moiety is selectedfrom the group comprising: phenyl, benzyl, indene, naphthalene,tetralin, decalin, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyland cycloheptyl.

By halo is meant fluoro, chloro, bromo or iodo.

Alkyl groups containing three or more carbon atoms may be straight,branched or cyclised.

In an embodiment R¹ is as defined above with the exception of whereinany substituent containing a heterocyclic ring bears one or two oxo orthioxo substituents on said ring; and R¹⁴ and R¹⁵ are as defined abovewith the exception of wherein they together with the nitrogen atom towhich they are attached represent a 5- or 6-membered ring and said ringbears one or two oxo or thioxo substituents; save that R¹ may represent4-pyridon-1-yl, 4-pyridon-1-yl-C₁₋₄ alkyl, 4-pyridon-1-yl-C₂₋₄ alkoxy,4-pyridon-1-yl-C₂₋₄ alkylamino, 2-oxopyrrolidin-1-yl or2,5-dioxopyrrolidin-1-yl.

In an embodiment, X is N.

In a further embodiment, Y is NR^(b), NR^(b)(CH₂), or (CH₂)NR^(b),preferably Y is NR^(b) and R^(b) is preferably hydrogen or methyl.

In a further embodiment R″ is a 5- or 6-membered heterocyclic ring asdefined above, optionally substituted by one or more R¹ groups selectedfrom the group comprising amino, hydrogen, halogen, hydroxy, formyl,carboxy, cyano, nitro, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio, C₁₋₈alkylsulphinyl, C₁₋₈ alkylsulphonyl, C₁₋₄ alkylamino, C₁₋₄ dialkylamino,dioxolanyl, hydroxy-C₁₋₄ alkyl or hydroxy-C₁₋₄ alkanoyl-(C₁₋₄alkyl)-amino.

In a further embodiment, n is 0 and each R¹ is selected from the groupcomprising amino, hydrogen, halogen, hydroxy, formyl, carboxy, cyano,nitro, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio, C₁₋₈ alkylsulphinyl,C₁₋₈ alkylsulphonyl, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, dioxolanyl,benzyloxy or hydroxy-C₁₋₄ alkanoyl-(C₁₋₄ alkyl)-amino.

In a preferred embodiment, n is 0, p is 1 and R¹ is selected from thegroup comprising amino, C₁₋₄ alkylamino, diC₁₋₄ alkylamino, especiallydiC₁₋₄ alkylamino, most especially dimethylamino or methylethylamino.

In a further embodiment, n is 0 and R¹ is selected from M¹-M²-M³-M⁴,M¹-M⁵ or M¹-M²-M^(3′)-M⁶ as defined above; and p=1.

In a further embodiment R″ is a 5- or 6-membered heterocyclic ring asdefined above substituted with an R¹ group selected from M¹-M²-M³-M⁴,M¹-M⁵ or M¹-M²-M^(3′)-M⁶ as defined above; and p=0.

In a further embodiment the group M²-M³-M⁴ represents an α-, β- orγ-amino carboxylic, sulphinic or sulphonic acid or a C₁₋₄ alkyl ester,an amide or a C₁₋₄ alkyl- or di-(C₁₋₄ alkyl)-amide thereof.

Preferably M¹ represents CH₂, CO, CH₂CH₂ or CH₂CO, more preferably CH₂.

Preferably M² represents NR¹² in which R¹² is as defined above; morepreferably R¹² represents H or methyl.

Preferably M³ represents CH₂, CH₂CH₂ or propyl.

Preferably M^(3′) represents CH₂, ethyl, propyl, isopropyl or is absent.

Preferably M⁴ represents SOR¹³, SO₂R¹³, NR¹²SO₂R¹³, CO₂R¹³ or CONR¹⁴R¹⁵in which R¹² and R¹³ are defined above and R¹⁴ and R¹⁵ eachindependently represent H or C₁₋₄ alkyl; more preferably R¹², R¹³, R¹⁴and R¹⁵ each independently represent H or methyl.

Preferably M⁵ represents a group NR¹⁴R¹⁵ in which R¹⁴ and R¹⁵ togetherwith the nitrogen atom to which they are attached represent a 6-memberedring optionally containing an additional heteroatom selected from N orO, in which ring any nitrogen atom present may optionally be substitutedwith a C₁₋₄ alkyl group, preferably a methyl group; or M⁵ represents agroup

in which t represents 2 or 3 and R¹⁶ represents OH, NH₂, N(C₁₋₄ alkyl)₂or OC₁₋₄ alkyl; more preferably R¹⁶ represents NH₂ or N(CH₃)₂.

M⁵ also preferably represents a group NR¹⁴R¹⁵ in which R¹⁴ and R¹⁵ eachindependently represent hydrogen or C₁₋₄ alkyl, more preferablyhydrogen, methyl, ethyl or isopropyl.

Preferably M⁶ represents a group NR¹⁴R¹⁵ in which R¹⁴ and R¹⁵ eachindependently represent C₁₋₄ alkyl, more preferably methyl, or R¹⁴ andR¹⁵ together with the nitrogen atom to which they are attached representa 5- or 6-membered ring optionally containing an additional heteroatomselected from N or O, in which ring any nitrogen atom present mayoptionally be substituted with a C₁₋₄ alkyl group, preferably a methylgroup; or M⁶ represents a 5- or 6-membered heterocyclic ring systemcontaining 1 or 2 heteroatoms selected from N or O.

In a further preferred embodiment M²-M³-M⁴ represents an α-aminocarboxylic acid or a methyl ester or amide thereof.

In a further preferred embodiment M²-M³-M⁴ represents an α-, β- orγ-amino sulphinic or sulphonic acid, more preferably a β- or γ-aminosulphinic or sulphonic acid, most preferably a β-aminosulphonic acid, ora methyl ester thereof.

In an especially preferred embodiment M²-M³-M⁴ represents amethylsulphonylethylamino, methylsulphinylethylamino,methylsulphonylpropylamino, methylsulphinylpropylamino,methylsulphonamidoethylamino, sarcosinamide, glycine, glycinamide,glycine methyl ester or acetylaminoethylamino group.

In a further especially preferred embodiment M⁵ represents apiperazinyl, methylpiperazinyl, piperidinyl, prolinamido orN,N-dimethylprolinamido group.

In a further especially preferred embodiment M⁵ represents anisopropylamino or N-morpholinyl group.

In a further especially preferred embodiment M¹-M⁵ represents anisopropylacetamido or N-morpholinoacetamido group.

In a further especially preferred embodiment M²-M^(3′)-M⁶ represents apyridylamino, cyclopropylamino, N-(piperidin-4-yl)-N-methylamino,N,N-dimethylaminoprop-2-ylamino, N-(2-dimethylaminoethyl)-N-ethylaminoor tetrahydrofuranomethylamino group, preferably a pyridylamino group.

In an embodiment R″ may be selected from the group comprising phenyl,furan, thiophene, pyridine, pyrimidine, pyrazine, pyrrole, oxazole,isoxazole, oxadiazole, thiazole, isothiazole, triazole, tetrazole andimidazole or a hydrogenated derivative of any of the aforementioned.

In a further preferred embodiment R″ may be selected from the groupcomprising phenyl, furan, imidazole, tetrazole, triazole, pyrrolidine,piperazine, piperidine and oxadiazole.

In a further embodiment each R¹ is independently selected from the groupcomprising amino, hydrogen, halogen, hydroxy, formyl, carboxy, cyano,nitro, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio, C₁₋₈ alkylsulphinyl,C₁₋₈ alkylsulphonyl, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, benzyloxy,hydroxy-C₁₋₄ alkyl, hydroxy-C₁₋₄ alkanoyl-(C₁₋₄ alkyl)-amino.

In an embodiment R² is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or halogen,preferably methyl or hydrogen, more preferably hydrogen.

In a further embodiment R⁴ is hydrogen, hydroxy, halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, di-[C₁₋₄ alkyl]amino, nitro or trifluoromethyl, preferablyhydrogen, halogen or methyl, more preferably hydrogen.

In a preferred embodiment R⁷ is an optionally substituted phenyl,dioxolanyl, thienyl, cyclohexyl or pyridyl group.

In a further embodiment, Z is absent or represents oxygen, CH₂, NR^(b),NR^(b)(CH₂), (CH₂)NR^(b), CH(CH₃), O(CH₂), (CH)CN, O(CF₂), (CH₂)O,(CF₂)O, S(CH₂), S(O)_(m), carbonyl or dicarbonyl, wherein R^(b) ishydrogen or C₁₋₄ alkyl.

In a preferred embodiment Z is oxygen, dicarbonyl, OCH₂, CH₂(CN), S(O)mor NR^(b), wherein R^(b) is hydrogen or C₁₋₄ alkyl.

In a further prefered embodiment R⁶ is benzyl,, halo-, dihalo- andtrihalobenzyl, α-methylbenzyl, phenyl, halo, dihalo- and trihalophenyl,pyridyl, pyridylmethyl, pyridyloxy, pyridylmethoxy, thienylmethoxy,dioxolanylmethoxy, cyclohexylmethoxy, phenoxy, halo-, dihalo- andtrihalophenoxy, phenylthio, benzyloxy, halo-, dihalo- andtrihalobenzyloxy, C₁₋₄ alkoxybenzyloxy, phenyloxalyl orbenzenesulphonyl, more preferably benzyl, fluorobenzyl, benzyloxy,fluorobenzyloxy, pyridylmethyl, phenyl, benzenesulphonyl, phenoxy orfluorophenoxy.

In a further embodiment R⁶ is in the para position with respect to Y.

When the group Z is absent, R⁶═R⁷.

In a further embodiment A represents

One or both of the rings comprising the mono or bicyclic ring system Umay be aromatic or non-aromatic. The R⁴ and R⁶ groups may be bound tothe ring system by either a carbon atom or a heteroatom of the ringsystem. The ring system itself may be bound to the bridging group by acarbon atom or a heteroatom. The R⁴ and R⁶ groups may be bound to eitherring when U represents a bicyclic ring system, but these groups arepreferably bound to the ring which is not bound to the bridging group Yin such a case.

Examples of suitable mono or bicyclic groups U include: isoindenyl,indenyl, indanyl, naphthyl, 1,2-dihydronaphthyl or1,2,3,4-tetrahydronaphthyl, pyrrolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, furanyl, 2H-pyranyl, thiophenyl, 1H-azepinyl,oxepinyl, thiepinyl, azocinyl, 2H-oxocinyl, thieno[2,3-b] furanyl,thianaphthenyl, indolyl, indolinyl, isoindolyl, isoindolinyl,indolizinyl, 1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl,1H-indazolyl, 2,3-dihydro-1H-indazolyl, benzoxazolyl,2,3-dihydrobenzoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl,2,3-dihydrobenzo[d]isoxazolyl, benzothiazoyl, 2,3-dihydrobenzothiazolyl,benzo[c]isothiazolyl, benzo[d]isothiazolyl,2,3-dihydrobenzo[d]isothiazolyl, 1H-benzotriazolyl, benzo[c]furanyl,benzo[c][1,2,3]thiadiazolyl, benzo[d][1,2,3]oxadiazolyl,benzo[d][1,2,3]thiadiazolyl, quinolyl, 1,2-dihydroquinolinyl,1,2,3,4-tetrahydroquinolinyl, isoquinolyl1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, 4H-1,4-benzoxazinyl, 2,3-dihydro-4H-1,4-benzoxazinyl,4H-1,4-benzothiazinyl or 2,3-dihydro-4H-1,4-benzothiazinyl.

Suitably U represents an indolyl, isoindolyl, indolinyl, isoindolinyl,1H-indazolyl, 2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl,2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group.

In an embodiment, the optional substitutents for the carbocyclic orheterocyclic moiety, which may be present at any available position ofsaid moiety, are selected from the group comprising:

(CH₂)_(q)S(O)_(m)—C₁₋₄alkyl, (CH₂)_(q)S(O)_(m)—C₃₋₆cycloalkyl,(CH₂)_(q)SO₂NR⁸R⁹, (CH₂)_(q)NR⁸R⁹, (CH₂)_(q)CO₂R⁸, (CH₂)_(q)OR⁸,(CH₂)_(q)CONR⁸R⁹, (CH₂)_(q)NR⁸COR⁹, (CH₂)_(q)COR⁸, (CH₂)_(q)R⁸, NR⁸SO₂R⁹and S(O)_(m)R⁸.

wherein q is an integer from 0 to 4 inclusive; m is 0, 1 or 2;

R⁸ and R⁹ are independently selected from the group comprising hydrogen,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, aryl, a 5- or 6-membered saturated orunsaturated heterocyclic ring which may be the same or different andwhich contains one or more heteroatoms which are selected from N, O orS(O)_(m), with the proviso that the heterocyclic ring does not containtwo adjacent O or S(O)_(m) atoms.

In a further embodiment the optional substitutents for the carbocyclicor heterocyclic moiety are selected from the group comprisingmorpholine, piperazine, piperidine, pyrrolidine, tetrahydrofuran,dioxolane, oxothiolane and oxides thereof, dithiolane and oxidesthereof, dioxane, pyridine, pyrimidine, pyrazine, pyridazine, furan,thiofuran, pyrrole, triazine, imidazole, trizole, tetrazole, pyrazole,oxazole, oxadiazole and thiadiazole.

Other optional substituents for the carbocyclic or heterocyclic moietyand also for other optionally substituted groups include, but are notlimited to, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, nitro,amino, cyano, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkyl carbonyl,carboxylate and C₁₋₄ alkoxy carboxyl.

In a further embodiment X represents N; A represents a pyridine ring; pis 0; n is 1; and the group R″ is in the 6-position of thepyridopyrimidine ring system.

In a further embodiment X represents N; A represents a pyridine ring; nis 0; p is 1; and the group R¹ is in the 6-position of thepyridopyridimidine ring system.

In a preferred embodiment of the present invention there is provided acompound of formula (I) or a salt or solvate thereof wherein Xrepresents N; Y represents NR^(a), wherein R^(a) is hydrogen or C₁₋₄alkyl; A represents a pyridine ring; R″ represents furan, thiophene,pyrrole, pyridine, pyrimidine, pyrazine, imidazole, oxazole, isoxazole,oxadiazole, tetrazole, triazole, dioxolane or a partially or fullyhydrogenated derivative of any of these groups, optionally substitutedby one or more R¹ groups selected from halo, C₁₋₄ alkyl, carboxy,formyl, hydroxy-C₁₋₄ alkyl, 1,3-dioxolan-2-yl, amino, C₁₋₄ alkylamino,di(C₁₋₄ alkyl)amino, hydroxy-C₁₋₄ alkanoyl(C₁₋₄ alkyl)amino, C₁₋₄alkylamino-C₁₋₄ alkyl or di(C₁₋₄ alkyl)amino-C₁₋₄ alkyl; p is 0; R²represents hydrogen; R⁴ represents hydrogen or methyl; U representsindolyl, benzimidazolyl or indazolyl, more preferably indazolyl; and R⁶represents phenyl, benzyl, α-methylbenzyl, fluorobenzyl,benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy.

In a further preferred embodiment of the present invention there isprovided a compound of formula (I) or a salt or solvate thereof whereinX represents N; Y represents NR^(a), wherein R^(a) is hydrogen or C₁₋₄alkyl; A represents a pyridine ring, R″ represents furan, thiophene,pyrrole, pyridine, pyrimidine, pyrazine, imidazole, oxazole, isoxazole,oxadiazole, tetrazole, triazole, dioxolane or a partially or fullyhydrogenated derivative of any of these groups, optionally substitutedwith an R¹ group selected from methylsulphonylethylaminomethyl,methylsulphonylethylamino-carbonyl, methylsulphinylethylamino-methyl,methylsulphinylethylamino-carbonyl, methylsulphonylpropylamino-methyl,methylsulphinylpropylamino-methyl, methylsulphonylpropyamino-carbonyl,methylsulphinylpropylamino-carbonyl,methylsulphonylethyl-(methylamino)-methyl,methylsulphonylethyl-(methylamino)-carbonyl,methylsulphinylethyl-(methylamino)-methyl,methylsulphinylethyl-(methylamino)-carbonyl,methylsulphonylpropyl-(methylamino)-methyl,methylsulphinylpropyl-(methylamino)-methyl,methylsulphonylpropyl-(methylamino)-carbonyl,methylsulphinylpropyl-(methylamino)-carbonyl,methylsulphonamidoethylamino-methyl,methylsulphonamidopropylamino-methyl, sarcosinamidomethyl,glycinylmethyl, glycinamidomethyl, glycinylmethyl methyl ester,acetylaminoethylaminomethyl, piperazinylmethyl, methylpiperazinylmethyl,piperidinylmethyl, N-(prolinamido)methyl,(N,N-dimethyl-prolinamido)methyl, pyridylaminomethyl,cyclopropylaminomethyl, N-(piperidin-4-yl)-N-methylaminomethyl,N,N-dimethylaminoprop-2-ylaminomethyl,N-(2-dimethylaminoethyl)-N-ethylaminomethyl, isopropylacetamido,N-morpholinylacetamido or tetrahydrofuranomethylaminomethyl andoptionally further substituted by one or more C₁₋₄ alkyl groups; p is 0;R² represents hydrogen; R⁴ represents hydrogen or methyl; U representsindolyl, benzimidazolyl or indazolyl, more preferably indazolyl; and R⁶represents phenyl, benzyl, α-methylbenzyl, fluorobenzyl,benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy.

In a further preferred embodiment of the present invention there isprovided a compound of formula (I) or a salt or solvate thereof, whereinX represents N; Y represents NR^(a) wherein R^(a) is hydrogen or C₁₋₄alkyl; A represents a pyridine ring; n is 0; each R¹ group is selectedfrom hydrogen, halo, C₁₋₄ alkyl, carboxy, formyl, hydroxy-C₁₋₄ alkyl,1,3-dioxolan-2-yl, benzyloxy, amino, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, hydroxy-C₁₋₄ alkanoyl(C₁₋₄ alkyl)amino, C₁₋₄alkylamino-C₁₋₄ alkyl, di(C₁₋₄ alkyl)amino-C₁₋₄ alkyl,methylsulphonylethylaminomethyl, methylsulphonylethylamino-carbonyl,methylsulphinylethylamino-methyl, methylsulphinylethylamino-carbonyl,methylsulphonylpropylamino-methyl, methylsulphinylpropylamino-methyl,methylsulphonylpropyamino-carbonyl, methylsulphinylpropylamino-carbonyl,methylsulphonylethyl-(methylamino)-methyl,methylsulphonylethyl-(methylamino)-carbonyl,methylsulphinylethyl-(methylamino)-methyl,methylsulphinylethyl-(methylamino)-carbonyl,methylsulphonylpropyl-(methylamino)-methyl,methylsulphinylpropyl-(methylamino)-methyl,methylsulphonylpropyl-(methylamino)-carbonyl,methylsulphinylpropyl-(methylamino)-carbonyl,methylsulphonamidoethylamino-methyl,methylsulphonamidopropylamino-methyl, sarcosinamidomethyl,glycinylmethyl, glycinamidomethyl, glycinylmethyl methyl ester,acetylaminoethylaminomethyl, piperazinylmethyl, methylpiperazinylmethyl,piperidinylmethyl, N-(prolinamido)methyl,(N,N-dimethyl-prolinmido)methyl, pyridylaminomethyl,cyclopropylaminomethyl, N-(piperidin-4-yl)-N-methylaminomethyl,N,N-dimethylaminoprop-2-ylaminomethyl,N-(2-dimethylaminoethyl)-N-ethylaminomethyl, isopropylacetamido,N-morpholinylacetamido or tetrahydrofuranomethylaminomethyl; R²represents hydrogen; R⁴ represents hydrogen or methyl; U representsindolyl, benzimidazolyl or indazolyl, more preferably indazolyl; and R⁶represents phenyl, benzyl, α-methylbenzyl, fluorobenzyl,benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy or fluorobenzyloxy.

In an especially prefered embodiment of the present invention there isprovided a compound of formula (I) or a salt or solvate thereof whereinX represents N; Y represents NR^(a), wherein R^(a) is hydrogen or C₁₋₄alkyl; A represents a pyridine ring; R″ represents a furan, imidazole,triazole, oxadiazole, pyrrolidine, piperidine or piperazine ring,optionally substituted by one or more R¹ groups selected from1,3-dioxolan-2-yl, formyl, carboxy, C₁₋₄-alkyl, prolinamidomethyl,isopropylacetamido, N-morpholinylacetamido,methylsulphonylethylaminomethyl or methylsulphonylethylaminocarbonyl; pis 0; R² represents hydrogen; R⁴ represents hydrogen or methyl; Urepresents indazolyl, indolyl or benzimidazolyl, more preferablyindazolyl; and R⁶ represents benzyl, fluorobenzyl, pyridylmethyl orbenzenesulphonyl.

In a further especially preferred embodiment of the present inventionthere is provided a compound of formula (I) or a salt or solvate thereofwherein X represents N; Y represents NR^(a), wherein R^(a) is hydrogenor C₁₋₄ alkyl; A represents a pyridine ring; n is 0; each R¹ group isselected from hydrogen, halo, benzyloxy, amino, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino or hydroxy-C₁₋₄ alkanoyl(C₁₋₄ alkyl)amino, more preferablydimethylamino; R² represents hydrogen; R⁴ represents hydrogen or methyl;U represents indazolyl, indolyl or benzimidazolyl, more preferablyindazolyl; and R⁶ represents benzyl, fluorobenzyl, pyridylmethyl orbenzenesulphonyl.

Preferred compounds of the present invention include:

(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

N4-(1-Benzyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

(1-Benzyl-1H-indazol-5-yl)-6-(N-(2-hydroxyethyl)-N-methylamino)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indazol-5-yl)-(pyrido[3,4-d]pyrimidin-4-yl)-amine;

(2-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

N4-(1-Benzyl-1H-indol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-(2-Benzyl-1H-benzimidazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]-pyrimidine-4,6-diamine;

(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-pyrido[3,4-d]-pyrimidin-4-yl)-amine;

5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;

(2S)-1-(5-(4-(1-Benzyl-1H-indazol-5-ylamino)-6-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-ylmethyl)-pyrrolidin-2-carboxylicacid amide;

(1-Benzyl-1H-indazol-5-yl)-(6-(3-methyl-3H-imidazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

N6,N6-Dimethyl-N4-(1-pyridin-2-ylmethyl-1H-indazol-5-yl)-pyrido[3,4-d]pyrimidine-4,6-diamine;

N6,N6-Dimethyl-N4-(1-pyridin-3-ylmethyl-1H-indazol-5-yl)-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-(1-Benzyl-3-methyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-(1-(2-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-(1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-(1-(4-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-(1-Benzenesulphonyl-1H-indol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-(3-Benzenesulphonyl-1H-indol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

(1-Benzyl-1H-indazol-5-yl)-(6-imidazol-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,4-triazol-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,3-triazol-2-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,3-triazol-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indazol-5-yl)-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indazol-5-yl)-(6-piperidin-1-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

N4-(1-Benzyl-1H-indazol-5-yl)-N6-ethyl-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

2-(4-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-piperazin-1-yl)-N-isopropyl-acetamide;

2-(4-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-piperazin-1-yl)-1-morpholin-4-yl-ethanone;

(1-Benzyl-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indazol-5-yl)-(6-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indazolyl-5-yl)-(6-benzyloxy-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesuphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido-[3,4-d]pyrimidin-4-yl)-amine;

5-[4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylicacid;

5-[4-(1-benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylicacid 2-methanesulphonyl-ethylamide;

N4-(1-Benzyl-1H-indazol-5-yl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-[1-(4-Hydroxybenzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

and salts or solvates thereof, particularly pharmaceutically acceptablesalts or solvates thereof.

Other preferred compounds of the present invention include:

N4-[1-(S,R-α-Methylbenzyl)-1H-indazol-5-yl]-N6,N6-dimethyl-pyrido-[3,4-d]pyrimidin-4,6-diamine;

N4-(3-Benzylsulphonyl-1H-indazol-6-yl)-N6,N6-dimethyl-pyrido[3,4-d]-pyrimidine-4,6-diamine;

N4-(3-Benzyl-1H-indazol-6-yl)-N6,N6-dimethyl-pyrido[3,4-d]-pyrimidine-4,6-diamine;

and salts or solvates thereof, particularly pharmaceutically acceptablesalts or solvates thereof.

Particularly preferred compounds of the present invention include:

N4-(1-Benzyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-(1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-(1-Benzyl-1H-indazol-5-yl)-N6-ethyl-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesuphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido-[3,4-d]pyrimidin-4-yl)-amine;

N4-(1-Benzyl-1H-indazol-5-yl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

and salts or solvates thereof, particularly pharmaceutically acceptablesalts or solvates thereof.

Certain compounds of formula (I) may exist in steroisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual steroisomers (enantiomers anddiastereoisomers) and mixtures of these are included within the scope ofthe present invention. Likewise, it is understood that compounds offormula (I) may exist in ntautomeric forms other than that shown in theformula and these are also included within the scope of the presentinvention.

Salts of the compounds of the present invention may comprise acidaddition salts derived from a nitrogen in the compound of formula (I).The therapeutic activity resides in the moiety derived from the compoundof the invention as defined herein and the identity of the othercomponent is of less importance although for therapeutic andprophylactic purposes it is, preferably, pharmaceutically acceptable tothe patient. Examples of pharmaceutically acceptable acid addition saltsinclude those derived from mineral acids, such as hydrochloric,hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, andorganic acids, such as tartaric, acetic, trifluoracetic, citric, malic,lactic, fumaric, benzoic, glycolic, gluconic, succinic andmethanesulphonic and arylsulphonic, for example p-toluenesulphonic,acids.

According to a further aspect of the present invention there is provideda process for the preparation of a compound of formula (I) as definedabove which comprises the steps:

(a) the reaction of a compound of formula (II)

wherein A, X, n, p and R² are as defined above and L, L′ and L″ aresuitable leaving groups, with a compound of formula (III)

UYH (III)

wherein U and Y are as defined above, to prepare a compound of formula(IV)

and subsequently (b) where n is 1, reaction with an appropriate reagentto substitute the group R″ onto the ring A by replacement of the leavinggroup L′; and (c) where p is other than 0, reaction with appropriatereagent(s) to substitute the group(s) R¹ onto the ring A by replacementof the leaving group(s) L″; and, if desired, (d) subsequently convertingthe compound of formula (I) thereby obtained into another compound offormula (I) by means of appropriate reagents.

Alternatively, the compound of formula (II) as defined above is reactedwith the appropriate reagents to substitute the groups R″ and R¹ ontothe ring A by replacement of the respective leaving groups and then theproduct thereby obtained (of formula (V) below) is reacted with thecompound of formula (III) as defined above, followed, if desired, byconversion of the compound of formula (I) thereby obtained into anothercompound of formula (I).

In a variant of this alternative the compound of formula (V)

may be prepared by the reaction of a compound of formula (VI)

with appropriate reagents to substitute the group(s) R¹ and the group R″onto the ring A to prepare a compound of formula (VII)

and subsequent reaction to incorporate the leaving group L. For example,a chloro leaving group can be incorporated by reaction of acorresponding 3,4-dihydropyrimidone with carbontetrachloride/triphenylphosphine in an appropriate solvent.

Simplified versions of these general processes will apply where either(i) p is 0 and n is 1 or (ii) where n is 0 and p is other than 0.

The group R″ may, therefore, be substituted onto the ring A byreplacement of a suitable leaving group. This is especially suitable forpreparing compounds where R″ is a substituted or unsubstituted phenyl orheterocyclic ring system; such compounds may, for example, be preparedby reaction of the corresponding aryl or heteroaryl stannane derivativewith the corresponding compound of formula (IV) carrying the leavinggroup L′ in the appropriate position on the ring.

The group(s) R¹ may, therefore, also be substituted onto the ring A byreplacement of suitable leaving group(s). This is especially suitablefor preparing compounds of formula (I) wherein an R¹ group is linked tothe ring A by a nitrogen atom; such compounds may, for example, beobtained by reaction of the amine corresponding to the group R¹ with thecorresponding compound carrying a halo substituent in the appropriateposition on the ring A.

The reagents used to effect the substitution of the groups R″ and R¹onto the ring A may, in certain circumstances, include appropriateprotecting group(s) well known to the person skilled in the art forparticular functionalities. This may, for example, be suitable whereeither of the groups R″ or R¹ contain a free amino functionality. Suchprotecting group(s) would be removed by standard methods after thesubstitution onto the ring A has been effected. For a description ofprotecting groups and their use see T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, 2nd edn., John Wiley & Sons,New York, 1991.

According to a further aspect of the present invention there is provideda process for the preparation of a compound of formula (I) as definedabove which comprises the steps:

(a) reacting a compound of formula (IV) as defined above withappropriate reagent(s) to prepare a compound wherein either the group L′(when n=1) or the group(s) L″ (when p is other than 0) is(are) replacedwith an appropriately functionalised group Z;

and (b) subsequently converting the group Z into the group R″ where L′has been replaced or into the group R¹ where L″ has been replaced bymeans of appropriate reagent(s);

(c) reacting with appropriate reagents to substitute the other of R¹ andR″ onto the ring A by replacement of the remaining leaving group L″ andL′ respectively, if present;

and, if desired, (d) subsequently converting the compound of formula (I)thereby obtained into another compound of formula (I) by means ofappropriate reagents.

Such processes are particularly suitable for the preparation ofcompounds of formula (I) wherein either r″ carries or R¹ represents asubstituent selected from M¹-M²-M³-M⁴, M¹-M⁵ or M¹-M²-M^(3′)-M⁶ asdefined above in which M² represents NR¹². In such cases preferably thegroup Z carries a terminal formyl group (CHO).

Such processes are especially suitable for the preparation of compoundsof formula (I) wherein either (i) p is 0, n is 1 and R″ carries asubstituent selected from M¹-M²-M³-M⁴, M¹-M⁵ or M¹-M²-M^(3′)-M⁶ asdefined above in which M² represents NR¹², or (ii) p is 1, n is 0 and R¹is selected from M¹-M²-M³-M⁴, M¹-M⁵ or M¹-M²-M^(3′)-M⁶ as defined abovein which M² represents NR¹².

Where Z carries a formyl group the compound may be suitably preparedfrom the corresponding dioxolanyl substituted compound, for example byacid hydrolysis. The dioxolanyl substituted compound may be prepared byreaction of a compound of formula (IV) with an appropriate reagent tosubstitute the relevant leaving group with the substituent carrying thedioxolanyl ring. This reagent could, for example, be an appropriateheteroaryl stannane derivative.

Where Z carries a terminal formyl group the compound could suitably beprepared by reaction of a compound of formula (IV) with an appropriateheteroaryl stannane derivative. This derivative is either readilyavailable or can be readily synthesised by those skilled in the artusing conventional methods of organic synthesis. Suitable possibilitiesfor preparation of compounds where R″ carries the aforementionedsubstituents include the following schematic examples:

The resulting compounds would, for example, then be converted into therespective stannane derivative.

Analogous methods could be used for phenyl and other heterocyclic ringsystems and also for the preparation of compounds where R¹ representsone of the aforementioned substituents.

Therefore a suitable process may comprise reaction of the compound inwhich the group Z carries a terminal formyl group (i.e. a —CHO or —(C₁₋₃alkylene)—CHO group) with a compound of formula HM²-M³-M⁴, a compound offormula HM²-M^(3′)-M⁶ or a compound of formula HM⁵, wherein M²represents NR¹². The reaction preferably involves a reductive aminationby means of an appropriate reducing agent, for example sodiumtriacetoxyborohydride.

A similar process would be involved where in M¹ one CH₂ group wasreplaced with a CO group and M² was NR¹². If necessary, in certaincircumstances, the ketone could be protected by standard methods toensure that the reductive amination involved the aldehyde functionality.

For the preparation of those compounds wherein in M¹ one CH₂ groupadjacent to M² is replaced with a CO group a suitable process wouldcomprise reaction of a compound in which the group Z carries a —(C₀₋₃alkylene)—CO₂H group with a compound of formula HM²-M³-M⁴, a compound offormula HM²-M^(3′)-M⁶ or a compound of formula HM⁵, wherein M²represents NR¹².

Alternatively, an analogous scheme to those described above could beused wherein the substitution of groups R″ and R¹ onto the ring A occursprior to the coupling reaction with the compound of formula (III).

According to a further alternative process the group Z is converted intothe group R″ by a de novo synthesis of a substituted or unsubstitutedheterocyclic ring system using appropriate reagents. Such a processwould involve standard synthetic methodology known to the person skilledin the art for building up the heterocyclic ring system.

For example, Z could suitably represent an alkyne group which whenreacted with an appropriate nitrile oxide results in the formation of anisoxazole ring system; reaction with an azide would result in theformation of a triazole ring system. The group Z could also suitablyrepresent an amidoxime group (derived from a cyano group) which whenreacted with an activated carboxylic acid derivative (such as an acidchloride or an acid imidazolide) would result in the formation of a1,2,4-oxadiazole ring system. The group Z could also suitably representa bromomethylenecarbonyl group which would be reacted with an imidate toresult in the formation of an oxazole ring system, with a guanidinogroup to result in the formation of an N-imidazole ring system or withan amidine group to result in the formation of a C-imidazole ringsystem. The group Z could also suitably represent an activatedcarboxylic acid group which would be reacted to form a hydrazinoketonewhich would subsequently be reacted with another activated carboxylicacid derivative to result in the preparation of a 1,3,4-oxadiazole ringsystem. Thus reaction of a compound carrying a relevant Z group withappropriate reagents carrying one of

—C═N═O, —NH—C(NH₂)═NH, —COX, —C(NH₂)═NOH, —C(OMe)═NH, or

—C(NH₂)═NH as a terminal group would result in the formation of the ringsystems indicated above.

Alternatively, an analogous scheme to those described above could beused wherein the substitution of the group R″ onto the ring A occursprior to the coupling reaction with the compound of formula (III).

The following scheme outlines, for example, the synthesis of derivativescarrying a substituted 1,3,4-oxadiazole ring as an R″ substituent:

Such processes are particularly suitable for the preparation of thecompounds of formula (I) wherein R″ carries a substituent selected fromM¹-M²-M³-M⁴, M¹-M⁵ or M¹-M²-M^(3′)-M⁶ as defined above in which M²represents CR¹²R¹³, including those in which in M¹ one CH₂ group isreplaced by a CO group.

Such processes are especially suitable for the preparation of compoundsof formula (I) wherein either (i) p is 0, n is 1 and R″ carries asubstituent selected from M¹-M²-M³-M⁴, M¹-M⁵ or M¹-M²-M^(3′)-M⁶ asdefined above in which M² represents CR¹²R¹³, or (ii) p is 1, n is 0 andR¹ is selected from M¹-M²-M³-M⁴, M¹-M⁵ or M¹-M²-M^(3′)-M⁶ as definedabove in which M² represents CR¹²R¹³.

Suitable leaving groups for L, L′ and L″ will be well known to thoseskilled in the art and include, for example, halo such as chloro andbromo; sulphonyloxy groups such as methanesulphonyloxy andtoluene-p-sulphonyloxy; alkoxy groups; and triflate.

The coupling reaction referred to above with the compound of formula(III) is conveniently carried out in the presence of a suitable inertsolvent, for example a C₁₋₄ alkanol, such as isopropanol, a halogenatedhydrocarbon, and ether, an aromatic hydrocarbon or a dipolar aproticsolvent such as acetone or acetonitrile at a non-extreme temperature,for example from 0 to 150°, suitably 10 to 100° C., preferably 50 to100° C.

Optionally, the reaction is carried out in the presence of a base whenY═NH. Examples of suitable bases include an organic amine such astriethylamine, or an alkaline earth metal carbonate, hydride, orhydroxide, such as sodium or potassium carbonate, hydride or hydroxide.When YH═OH or SH it is necessary to perform the reaction in the presenceof a base, and in such a case the product is not obtained as the salt.

The compound of formula (I) in the case in which Y═NR^(b) may beobtained from this process in the form of a salt with the acid HL,wherein L is as hereinbefore defined, or as the free base by treatingthe salt with a base as hereinbefore defined.

The compounds of formulae (II) and (III) as defined above, the reagentsto substitute the group(s) R¹ and the group R″, and the reagent(s) toconvert the group Z into the group R¹ or R″ are either readily availableor can be readily synthesised by those skilled in the art usingconventional methods of organic synthesis.

As indicated above, the compound of formula (I) prepared may beconverted to another compound of formula (I) by chemical transformationof the appropriate substituent or substituents using appropriatechemical methods (see for example, J. March “Advanced OrganicChemistry”, Edition III, Wiley Interscience, 1985).

For example, a group R¹ may be substituted onto the ring A byreplacement of another group R¹ which is a suitable leaving group. Thisis especially suitable for preparing compounds of formula (I) wherein anR¹ group is linked to the ring A by a nitrogen atom; such compounds may,for example, be obtained by reaction of the amine corresponding to thegroup R¹ with the corresponding compound of formula (I) carrying a halosubstituent in the appropriate position on the ring A.

Similarly a group R″ may be substituted onto the ring A by replacementof a group R¹ which is a suitable leaving group. This is especiallysuitable for preparing compounds where R″ is a phenyl or heterocyclicring system; such compounds may, for example, be prepared by reaction ofthe corresponding aryl or heteroaryl stannane derivative with thecorresponding compound of formula (I) carrying a halo substituent in theappropriate position on the ring A.

For example, a compound containing an alkyl or aryl mercapto group maybe oxidised to the corresponding sulphinyl or sulphonyl compound by useof an organic peroxide (e.g. benzoyl peroxide) or suitable inorganicoxidant (eg OXONE®).

A compound containing a nitro substituent may be reduced to thecorresponding amino-compound, e.g. by use of hydrogen and an appropriatecatalyst (if there are no other susceptible groups) or by use of RaneyNickel and hydrazine hydrate.

Amino or hydroxy substituents may be acylated by use of an acid chlorideor an anhydride under appropriate conditions. Equally an acetate oramide group may be cleaved to the hydroxy or amino compound respectivelyby treatment with, for example, dilute aqueous base.

In addition reaction of an amino substituent with triphosgene andanother amine (eg aqueous ammonia, dimethylamine) gives the ureasubstituted product.

An amino substituent may also be converted to a dimethylaminosubstituent by reaction with formic acid and sodium cyanoborohydride.

A formyl substituent may be converted to a hydroxymethyl or a carboxysubstituent by standard reduction or oxidation methods respectively.

All of the above-mentioned chemical transformations may also be used toconvert one compound of formula (II) to a further compound of formula(II) prior to any subsequent reaction; or to convert one compound offormula (II) to a further compound of formula (III) prior to anysubsequent reaction.

Various intermediate compounds used in the above-mentioned processes,including but not limited to certain of the compounds of formulae (II),(III), (IV), (V), (VI) and (VII) as illustrated above, are novel andthus represent a further aspect of the present invention.

The compounds of formula (I) and salts thereof have anticancer activityas demonstrated hereinafter by their inhibition of the protein tyrosinekinase c-erbB-2, c-erbB-4 and/or EGF-r enzymes and their effect onselected cell lines whose growth is dependent on c-erbB-2 or EGF-rtyrosine kinase activity.

The present invention thus also provides compounds of formula (I) andpharmaceutically acceptable salts or solvates thereof for use in medicaltherapy, and particularly in the treatment of disorders mediated byaberrant protein tyrosine kinase activity such as human malignancies andthe other disorders mentioned above. The compounds of the presentinvention are especially useful for the treatment of disorders caused byaberrant c-erbB-2 and/or EGF-r activity such as breast, ovarian,gastric, pancreatic, non-small cell lung, bladder, head and neckcancers, and psoriasis.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from a disorder mediated by aberrantprotein tyrosine kinase activity, including susceptible malignancies,which comprises administering to said subject an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, in therapy.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, in the preparation of a medicament for the treatment of cancerand malignant tumours.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, in the preparation of a medicament for the treatment ofpsoriasis.

Whilst it is possible for the compounds, salts or solvates of thepresent invention to be administered as the new chemical, it ispreferred to present them in the form of a pharmaceutical formulation.

According to a further feature of the present invention there isprovided a pharmaceutical formulation comprising at least one compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, together with one or more pharmaceutically acceptable carriers,diluents or excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain for example 0.5 mg to 1 g, preferably 70 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I)depending on the condition being treated, the route of administrationand the age, weight and condition of the patient.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318(1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists which may be generated by means ofvarious types of metered dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

Preferred unit dosage formulations are those containing a daily dose orsub-dose, as herein above recited, or an appropriate fraction thereof,of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

The animal requiring treatment with a compound, salt or solvate of thepresent invention is usually a mammal, such as a human being.

A therapeutically effective amount of a compound, salt or solvate of thepresent invention will depend upon a number of factors including, forexample, the age and weight of the animal, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration, and will ultimately be at the discretion ofthe attendant physician or veterinarian. However, an effective amount ofa compound of the present invention for the treatment of neoplasticgrowth, for example colon or breast carcinoma will generally be in therange of 0.1 to 100 mg/kg body weight of recipient (mammal) per day andmore usually in the range of 1 to 10 mg/kg body weight per day. Thus,for a 70 kg adult mammal, the actual amount per day would usually befrom 70 to 700 mg and this amount may be given in a single dose per dayor more usually in a number (such as two, three, four, five or six) ofsub-doses per day such that the total daily dose is the same. Aneffective amount of a salt or solvate of the present invention may bedetermined as a proportion of the effective amount of the compound perse.

The compounds of the present invention and their salts and solvates maybe employed alone or in combination with other therapeutic agents forthe treatment of the above-mentioned conditions. In particular, inanti-cancer therapy, combination with other chemotherapeutic, hormonalor antibody agents is envisaged. Combination therapies according to thepresent invention thus comprise the administration of at least onecompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof and at least one other pharmaceutically active agent. Thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) may be administered together or separately and, whenadministered separately this may occur simultaneously or sequentially inany order. The amounts of the compound(s) of formula (I) and the otherpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect.

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

¹H NMR spectra were obtained at 500 MHz on a Bruker AMX500spectrophotometer, on a Bruker spectrophotometer at 300 Mz, or on aBruker AC250 or Bruker AM250 spectrophotometer at 250 MHz. J values aregiven in Hz. Mass spectra were obtained on one of the followingmachines; VG Micromass Platform (electrospray positive or negative),HP5989A Engine (thermospray positive) or Finnigan-MAT LCQ (ion trap)mass spectrometer. Analytical thin layer chromatography (tlc) was usedto verify the purity of some intermediates which could not be isolatedor which were too unstable for full characterisation, and to follow theprogess of reactions. Unless otherwise stated, this was done usingsilica gel (Merck Silica Gel 60 F254). Unless otherwise stated, columnchromatography for the purification of some compounds used Merck Silicagel 60 (Art. 1.09385, 230-400 mesh), and the stated solvent system underpressure.

Petrol refers to petroleum ether, either the fraction boiling at 40-60°C., or at 60-80° C.

Ether refers to diethylether.

DMAP refers to 4-dimethylaminopyridine.

DMF refers to dimethylformamide.

DMSO refers to dimethylsulphoxide.

THF refers to tetrahydrofuran.

TMEDA refers to N,N,N′,N′-tetramethylethylenediamine.

TFA refers to trifluoroacetic acid.

HPLC refers to high pressure liquid chromatography.

RT refers to retention time.

Useful preparative techniques are described in WO96/09294, WO97/03069and WO97/13771; also described in these publications are appropriateintermediate compounds other than those detailed below.

General Procedures

(A) Reaction of an amine with a bicyclic species containing a4-chloropyrimidine ring

The optionally substituted bicyclic species and the specified amine weremixed in an appropriate solvent (acetonitrile unless otherwisespecified), and heated to reflux. When the reaction was complete (asjudged by tlc), the reaction mixture was allowed to cool. The resultingsuspension was diluted, e.g. with acetone, and the solid collected byfiltration, washing e.g. with excess acetone, and dried at 60° C. invacuo, giving the product as the hydrochloride salt. If the free basewas required (e.g. for further reaction), this was obtained by treatmentwith a base e.g. triethylamine; purification by chromatography was thenperformed, if required.

(B) Reaction of a product from Procedure (A) with a heteroaryl tinreagent

A stirred mixture of the product from Procedure (A), (containing asuitable leaving group such as chloro, bromo, iodo or triflate), aheteroaryl stannane and a suitable palladium catalyst, such asbis-(triphenylphosphine)palladium (II) chloride or1,4-bis(diphenylphosphino)-butane palladium (II) chloride (prepared asdescribed in C. E. Housecroft et. al., Inorg. Chem., (1991), 30(1),125-130), together with other appropriate additives, were heated atreflux in dry dioxane or another suitable solvent under nitrogen untilthe reaction was complete. The resulting mixture was generally purifiedby chromatography on silica.

(C) Reaction of the product from Procedure (A) with a second amine

The product of Procedure (A) (containing a suitable leaving group suchas chloro) was dissolved in an excess of the desired amine (or asolution thereof) and heated in a pressure vessel (e.g. at 130° C. for17 hr). The cooled mixture was generally purified by chromatography onsilica.

Preparation of Intermediates

1-Benzyl-5-nitro-1H-indole

Dry dimethylsulphoxide (20 ml) was added to potassium hydroxide (4.2 g,0.074 mol) (crushed pellets) and the mixture was stirred under nitrogenfor 5 mins. 5-Nitroindole (commerically available) (3.0 g, 0.019 mol)was then added and the red mixture stirred for 30 min at roomtemperature. The mixture was then cooled to −10° C., benzyl bromide (4.4ml, 0.037 mol) was slowly added and the mixture stirred and allowed towarm to room temperature over a period of 40 mins. Water (50 ml) wasthen added and the mixture was extracted with diethyl ether (2×200 ml).The extracts were washed with water (4×50 ml), dried over sodiumsulphate and evaporated to leave an oily solid. The excess benzylbromide was removed by dissolving the whole in diethyl ether (50 ml),diluting this solution with 40-60 petrol (50 ml) and then graduallyremoving the diethyl ether in vacuo to leave a yellow solid suspended inthe petrol. The solid was filtered, washed with copious amounts of 40-60petrol and dried to give 1-benzyl-5-nitroindole (2.4 g, 51%) as a yellowsolid, m.p. 102-104° C.; δH [²H₆]-DMSO 8.53 (1H, s, 4-H), 8.00 (1H, d, J9, 6-H), 7.78 (1H, s, 2-H), 7.68 (1H, d, J 9, 7-H), 7.36-7.20 (5H, m,2′-H, 3′-H, 4′-H, 5′-H, 6′-H), 6.81 (1H, s, 3-H), 5.52 (2H, s, CH₂).

5-Amino-1-benzyl-1H-indole

A solution of 1-benzyl-5-nitroindole (0.51 g, 0.02 mol) in a mixture ofethyl acetate (25 ml) and methanol (25 ml) was carefully added to 10%palladium on charcoal (45 mg). The resulting suspension was stirred atroom temperature under an atmosphere of hydrogen. When the reaction wascomplete (indicated by tic or calculated uptake of hydrogen) thesuspension was filtered through a pad of Hyflo™, and the filtrateevaporated to dryness to give 5-amino-1-benzylindole (0.40 g, 91%) as anoff-white solid; m.p. 66-68° C.; δH [²H₆]-DMSO 7.30-7.12 (6H, m, 2-H,2″-H, 3″-H, 4″-H, 5″-H, 6″-H), 7.08 (1H, d, J 8, 7-H), 6.70 (1H, s,4-H), 6.49 (1H, d, J 8, 6-H), 6.18 (1H, s, 3-H), 5.28 (2H, s, CH₂), 4.38(2H, br s, NH₂).

2-Benzyl-5-nitro-1H-benzimidazole

A misture of 4-nitro-o-phenylene diamine (1.54 g) and phenylacetic acid(2.04 g) in 5N aqueous HCl (16 ml) were heated at 110° C. under nitrogenfor 22 hours. The mixture was cooled to room temperature and theaccumulated black solid collected by filtration. This crude residue wasthen adsorbed onto silica and chromatographed to give the title compound(0.84 g) as a purple foam; δH CDCl₃ 9.70 (1H, bs), 8.15 (1H, d), 7.30(7H, m), 4.30 (2H, s); m/z (M+1)⁺254.

5-Amino-2-benzyl-1H-benzimidazole

The title compound was prepared from 5-nitro-2-benzylbenzimidazole by ananalogous reduction method to that described above for5-amino-1benzyl-1H-indole; m/z (M+1)⁺224. Also note the published method(J. Het. Chem., 23, 1109-13, (1986)).

1-N-Benzyl-5-nitro-1H-indzole and 2-N-Benzyl-5-nitro-1H-indazole

A stirred mixture of 5-nitroindazole (50 g), potassium carbonate (46.6g, 1.1 equiv.) and benzyl bromide (57.6 g, 1.1 equiv) inN,N-dimethylformamide (500 ml) was heated at 75° C. for a period of 4hours. The reaction was then cooled and water (500 ml) was graduallyadded to precipitate the product which was filtered off and washed withwater (50 ml) and dried in the air at ambient temperature. The weight ofpale yellow solid thus obtained was 72.3 g (93%), m.pt. 95-97° C.; HPLC(Partisil 5, dichloromethane, 4 ml/min, 250 nm) gave an isomer ratio(1-N-benzyl:2-N-benzyl) of 63:37 (RT-1N3.4 min, RT-2N6.6 min). To afiltered solution of the mixed regioisomers (100 g) in acetone (470 ml)at room temperature was added, gradually with stirring, water (156 ml)and the mixture was stirred for one hour. The resultant yellowcrystalline solid was filtered off and dried in the air at ambienttemperature to give 36.4 g (34%) of material; m.pt. 124-126° C.; HPLCshowed an isomer ratio (1-N-benzyl:2-N-benzyl) of 96:4; δH (CDCl₃) 5.58(2H, s, CH₂), 7.12-7.15(2H)&7.22-7.29(3H)-(phenyl), 7.33(1H,dt,J=1 Hz &9 Hz, H-7), 8.15(1H,dd,J=2 Hz & 9 Hz, H-6), 8.19(1H,d,J=1 Hz, H-3), 8.67(1H,dd,J=1 Hz & 2 Hz, H-4).

also note the published method in FR 5600, Jan. 8, 1968.

5-Amino-1-N-benzyl-1H-indazole

1-Benzyl-5-nitroindazole (400 g) was suspended in ethanol (5 liter) andhydrogenated in the presence of 5% platinum on carbon catalyst (20 g)operating at 1 bar pressure and 50-60° C. When hydrogen uptake wascomplete the reactor contents were heated to 70° C., discharged andfiltered while still hot and the filtrate concentrated to ˜4 liter whichcaused some crystallisation. Water (4 liter) was then gradually addedwith stirring and the mixture was stirred at 5° C. overnight. Theresultant crystals were filtered off and air-dried at ambienttemperature to give 305 g (86%) of material, m.pt. 150-152° C.; HPLC(Supelcosil ABZ+, gradient 0.05% trifluoroacetic acid in water/0.05%trifluoroacetic acid in acetonitrile, 1.5 ml/min, 220 nm) showed<1% ofthe corresponding 2-N-isomer (RT-1N 6.03 min, RT-2N 5.29 min); δH(CDCl₃) 3.3-3.8(2H,broad s,NH₂), 5.47 (2H,s,CH₂), 6.74(1H,dd,J=2 Hz & 9Hz,H-6), 6.87(1H,dd,J=1 Hz & 2 Hz,H-4), 7.06-7.11(3H) &7.17-7.25(3H)-(phenyl & H-7), 7.77(1H,d,J=1 Hz, H-3).

Also note the published method in FR 5600, Jan. 8, 1968.

1-Benzyl-3-methyl-5-nitro-1H-indazole

2-Fluoro-5nitroacetophenone (H. Sato et al, Bioorganic and MedicinalChemistry Letters, 5(3), 233-236, 1995) (0.24 g) was treated withtriethylamine (0.73 ml) and benzyl hydrazine dihydrochloride (0.255 g)in ethanol (20 ml) at reflux under N₂ for 8 days. The mixture was cooledand the solid 1-benzyl-3-methyl-5-nitroindazole (0.16 g) was collectedby filtration; m/z (M+1)⁺268.

1-Benzyl-3-methyl-1H-indazol-5-ylamine

1-Benzyl-3-methyl-5-nitroindazole (0.15 g) in THF (15 ml) was treatedwith platinum on carbon (0.05 g, 5%) under an atmosphere of hydrogen atroom temperature. When hydrogen uptake was complete, the mixture wasfiltered and concentrated in vacuo to give the title compound; m/z(M+1)⁺268.

Further amino-indazole intermediates

The relevant nitro-substituted 1H-indazole was treated with a base suchas potassium carbonate or sodium hydroxide in a suitable solvent, suchas acetone or acetonitrile. The appropriate aryl halide or heteroarylhalide was added and the reaction mixture heated or stirred at roomtemperature overnight. Subsequent concentration in vacuo andchromatography on silica gave the desired 1-substitutednitro-1H-indazoles. Hydrogenation was carried out by analogy with thepreparation of 5-amino-1benzyl-1H-indole described above.

Amines prepared by such methods and specifically used in the preparationof the later Examples include:

5-Amino-1-benzyl-1H-indazole; m/z (M+1)⁺224

5-Amino-1-(2-fluorobenzyl)-1H-indazole; m/z (M+1)⁺242

5-Amino-1-(3-fluorobenzyl)-1H-indazole; m/z (M+1)⁺242

5-Amino-1-(4-fluorobenzyl)-1H-indazole; m/z (M+1)⁺242

5-Amino-1-(2-pyridylmethyl)-1H-indazole; m/z (M+1)⁺225

5-Amino-1-(3-pyridylmethyl)-1H-indazole; m/z (M+1)⁺225

5-Amino-1-(2,3-difluorobenzyl)-1H-indazole; m/z (M+1)⁺260

5-Amino-1-(3,5-difluorobenzyl)-1H-indazole; m/z (M+1)⁺260.

Other amines prepared by such methods include:

5-Amino-1-(4-pyridylmethyl)-1H-indazole; m/z (M+1)⁺225

1-Benzenesulphonylindol-5-yl-amine was prepared according to thepublished method (J. Org. Chem., 55, 1379-90, (1990)).

3-Benzenesulphonylindol-6-yl-amine

3-Benzenesulphonyl-6-nitroindole (K. Wojciechowski and M Makosza, Tet.Lett., 25 (42), p4793, 1984) was hydrogenated by analogy with theprocedures above to give the title compound; δH [²H₆]DMSO 11.64 (1H,s),7.94 (2H,m), 7.81 (1H,s), 7.57 (3H, m), 7.49(1H,d), 6.60(1H,s), 6.55(1H,dd), 5.40 (2H,s).

N-5-[N-tert-Butoxycarbonyl)amino]-2-chloropyridine

A stirred solution of 6-chloronicotinic acid (47.3 g),diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol(240 ml) were heated under reflux under nitrogen for 2.5 hours. Thesolution was cooled and concentrated in vacuo. The syrupy residue waspured into 3 liters of a rapidly stirred solution of 0.33N aqueoussodium carbonate. The precipitate was stirred for one hour and filtered.The solid was washed with water and dried in vacuo at 70° C. to give thetitle compound (62 g) as a pale brown solid; m.p. 144-146° C.; δH[²H₆]-DMSO 8.25(1H,d), 7.95 (1H,bd), 7.25 (1H,d), 6.65(1H,bs), 1.51(9H,s); m/z (M+1)⁺229.

This material may subsequently be carried forward to the appropriatelysubstituted pyridopyrimidine intermediate according to the procedures asdescribed in WO95/19774, J. Med. Chem., 1996, 39, pp 1823-1835, and J.Chem. Soc., Perkin Trans. 1, 1996, pp 2221-2226. Specific compounds madeby such procedures include 6-chloro-pyrido[3,4-d]pyrimidin-one and4,6-dichloro-pyrido[3,4-d]pyrimidine.

2-N,N-Dimethylamino-4-nitropyridine

2-Chloro-4-nitropyridine (0.64 g) was treated with aqueous dimethylamine(10 ml, 25%) at reflux for 30 minutes. The mixture was diluted withwater and filtered. The solid was washed with water and dried in vacuoto give the title compound (0.67 g); δH [²H₆]DMSO 9.05 (1H,d),8.30(1H,dd), 6.84(1H,d), 3.28 (6H,s).

2-N,N-Dimethylamino-4-aminopyridine

2-N,N-Dimethylamino-4-nitropyridine (0.67 g) in ethanol (50 ml) wasadded to 10% palladium on charcoal and stirred under an atmosphere ofhydrogen. When the reaction was complete, the suspension was filteredthrough a pad of Hyflo™ and the filtrate concentrated in vacuo to givethe title compound (0.49 g); δH [²H₆]DMSO 7.57 (1H,d), 6.88(1H,dd),6.41(1H,d), 4.39(2H,bs), 3.80 (6H,s); m/z (M+1⁺)138.

N-(4-N′,N′-Dimethylaminopyrid-3-yl)-2,2-dimethylpropionamide

2-N,N-Dimethylamino-4aminopyridine (1.37 g) in methylene chloride (20ml) under N₂ was treated with triethylamine (1.53 ml) and pivaloylchloride (1.32 g) over 5 minutes. After 16 hours at room temperature,the mixture was diluted with methylene chloride, washed with water,dried and concentrated to give the title compound (2.2 g); δH [²H₆]DMSO9.20(1H,s), 8.22 (1H,d), 7.70(1H,dd), 6.60(1H,d), 2.98(6H,s), 1.20(9H,s); m/z (M+1⁺)222.

2(N,N-Dimethylamino)-5-(2,2-dimethylpropionamido)-pyridine-4-carboxylicacid

N-(4-N′,N′-Dimethylaminopyrid-3-yl)-2,2-dimethylpropionamide (1.1 g) indry THF under N₂ at −70° C. was treated with TMEDA (1.45 g) and butyllithium (1.6M, 8 ml). The mixture was warmed to 0° C. for three hoursbefore being recooled to −70° C. Carbon dioxide was bubbled through thesolution for 1 hour and the resulting solution was warmed to roomtemperature under a carbon dioxide atmosphere and stirred there for 16hours. The resulting mixture was concentrated in vacuo and partitionedbetween ether and water. The aqueous layer was concentrated in vacuo togive the title compound (1.0 g); δH [²H₆]DMSO 13.50(1H,s), 9.22(1H,s),7.26(1H,s), 2.95(6H,s), 1.20 (9H,s); m/z (M+1⁺)266.

5-Amino-2-(N,N-dimethylamino)-pyridine-4-carboxylic acid

2-(N,N-Dimethylamino)-5-(2,2-dimethylpropionamido)-pyridine-4-carboxylicacid (0.8 g) was treated with 5N HCl at reflux for 5 hours. The mixturewas allowed to cool and evaporated to dryness to give the title compound(0.54 g);δH [²H₆]DMSO 8.15(1H,s), 7.35(2H,bs), 6.70(1H,s), 3.10(6H,s);m/z (M+1⁺)182.

6-(N,N-Dimethylamino)-pyrido[3,4-d]pyrimidin-4-one

5-Amino-2-(N,N-dimethylamino)-pyridine-4-carboxylic acid (0.54 g) wastreated with formamidine acetate (3.12 g) in glacial acetic acid (20 ml)and heated at reflux for 16 hours. The mixture was cooled, evaporated todryness in vacuo and partitioned between ethyl acetate and water. Theorganic phase was separated, dried over magnesium sulphate andconcentrated in vacuo to give, after chromatography on silica, the titlecompound (0.25 g); δH CDCl₃ 9.10(1H,d), 8.80(1H,s), 8.31(1H,s),7.07(1H,s), 3.20(6H,s); m/z (M+1⁺)191.

Alternatively, 6-chloro-pyrido[3,4-d]pyrimidin-4-one (26.14 g) wastreated with 2N dimethylamine in ethanol (200 ml) and heated at 130° C.in a Parr bomb for 3 days. The cooled mixture was filtered andtriturated from isopropanol to give the title compound (16.61 g) as ayellow solid; m/z (M+1⁺)191.

4-Chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine

6(N,N-Dimethylamino)-pyrido[3,4-d]pyrimidin-4-one (12 g) was carefullytreated with phosphorus oxychloride (42 ml) and triethylamine (18 ml) atroom temperature under N₂. After 1 hour at room temperature and 1 hourat 50° C., the mixture was concentrated in vacuo, azeotroping withtoluene, then taken up in ethyl acetate, washed with sodium bicarbonatesolution, dried and concentrated in vacuo to give the title compound(10.34 g); δH CDCl₃ 9.13(1H,s), 8.74(1H,s), 6.69(1H,s), 3.25(6H,s).

6-Cyano-pyrido[3,4-d]pyrimidin-4-one

6-Chloro-pyrido[3,4-d]pyrimidin-4-one (10 g) in 1-methyl-2-pyrrolidinone(100 ml) was treated with copper (I) iodide (10.52 g) and potassiumcyanide (7.10 g) at 215° C. for 72 hours under N₂. Further potassiumcyanide was added (3.58 g) and heating continued at 230° C. for 70hours. The 1-methyl-2-pyrrolidinone was removed by distillation atreduced pressure and the residue absorbed onto silica. Chromatographygave the title compound (2.4 g) as a beige solid; δH [²H₆]DMSO 13.0(1H,bs), 9.25 (1H,s), 8.55 (1H,s), 8.50 (1H,s); m/z (M+1⁺)171.

6-(1,2,3,4-Tetrazol-5-yl)-pyrido[3,4-d]pyrimidin-4-one

6-Cyano-pyrido[3,4-d]pyrimidin-4-one (0.3 g) in diglyme (2 ml) wastreated with tributyl tin azide (0.49 g) at reflux under N₂ for 15hours. The cooled mixture was partitioned between ethyl acetate andwater and the aqueous phase extracted further with ethyl acetate. Theaqueous phase was concentrated in vacuo, the residue taken up inmethanol and inorganics removed by filtration. Subsequent concentrationgave the title compound (1.4 g) as a beige solid; δH [²H₆]DMSO 8.96(1H,s), 8.50 (1H,s), 8.27 (1H,s); m/z (M+1⁺)216.

6-(5-Methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-one

6-(1,2,3,4-Tetrazol-5-yl)-pyrido[3,4-d]pyrimidin-4-one (1.4 g) in aceticanhydride (10 ml) was heated at reflux under N₂ for 2.5 hours. Thecooled mixture was absorbed onto silica and purified by chromatographyto give the title compound 90.14 g) as a beige solid; δH [²H₆]DMSO13.0(1H,bs), 9.30 (1H,s), 8.66 (1H,s), 8.47 (1H,s) 2.75 (3H,s); m/z(M+1⁺)230.

4-Chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidine

6-(5-Methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-one (0.5 g)was treated with phosphorus oxychloride at room temperature under N₂.After 1 hour at room temperature and 1 hour at 50° C., the mixture wasconcentrated in vacuo, azeotroping with toluene, then taken up in ethylacetate, washed with sodium bicarbonate solution, dried and concentratedin vacuo to give the title compound (0.17 g) as an orange solid; δHCDCl₃ 9.68 (1H,s), 9.30 (1H,s), 8.96 (1H,s), 2.75 (3H,s); m/z (M+1⁺)248.

6-Benzyloxy-4-hydroxy-pyrido[3,4-d]pyrimidine

Sodium hydride (8.14 g of 60% dispersion with mineral oil, 203.5 mmol)was suspended in bensyl alcohol (200 ml) under a nitrogen atmosphere.6-Chloropyrido[3,4-d]pyrimidine (9.081 g, 50.0 mmol) was added and themixture was heated at 150° C. for 18 hours. When cool, the mixture waspartitioned between water (200 ml) and ether (200 ml), the layers wereseparated, and the aqueous layer was washed with further ether. Theaqueous solution was then acidified to pH1 by the addition of dilute HClcausing the precipitation of the title compound as a cream solid (7.885g, 31.1 mmol, 62%); δH [²H₆]DMSO 8.71(1H,s), 7.89(1H,s), 7.25-7.48(6H,m), 5.40 (2H,s); m/z (M+1⁺)254.

6-Benzyloxy-4-chloro-pyrido[3,4-d]pyrimidine

6-Benzyloxy-4-hydroxy-pyrido[3,4-d]pyrimidine (1.033 g, 4.1 mmol) wassuspended in thionyl chloride (10 ml) under a nitogen atmosphere. DMF (3drops) was added and the mixture was heated to reflux with stirring for5.5 hours to give a dark solution, and then left to stand under nitrogenovernight. The mixture was concentrated in vacuo, azeotroping twice withtoluene to remove all traces of thionyl cloride and acidic by-products.The material was further dried for two hours in vacuo to give the titlecompound as a brown solid, used without further purification; δH[²H₆]DMSO 8.77(1H,s), 8.13(1H,s), 7.30-7.52 (6H,m), 5.45 (2H,s).

(3-Methyl-3-oxetane)methyl 2-furoate

2-Furoic acid (9.0 g, 80.3 mmol) was added to a solution of3-methyl-3-oxetanemethanol (16.5 g, 161.6 mmol),1,3-dicyclohexylcarbodiimide (25.0 g, 121.1 mmol) and DMAP (0.50 g, 4.1mmol) in dichloromethane (250 ml), and the mixture was stirred under anitrogen atmosphere overnight. The mixture was filtered, and thefiltrate was concentrated in vacuo to give an oil. Crystallisation fromethanol/water gave a white solid collected by filtration, which wasshown by NMR to be 2-furoic acid. The filtrate was concentrated in vacuoto remove the ethanol, and the resulting aqueous solution was extractedwith dichloromethane (x2). The combined dichloromethane extracts weredried (MgSO₄) and concentrated to give the title compound as acolourless oil (11.8 g, 60.1 mmol, 75%); δH [²H₆]DMSO 8.00 (1H,s), 7.34(1H,d), 7.71 (1H,dd), 4.44 (2H,d), 4.35 (2H,s), 4.28 (2H,d), 1.31(3H,s).

2-(4-Methyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)furan

3-Methyl-3-oxetane)methyl 2-furoate (11.8 g, 60.1 mmol) was dissolved indichloromethane (250 ml) and the solution was cooled to 0° C. Borontrifluoride-etherate (10 drops) was added and the mixture stirred atroom temperature, and then left to stand for two months. Triethylamine(0.5 ml, 0.36 g, 3.6 mmol) was added and the mixture concentrated togive a sticky white solid. Trituration with ether/acetone gave the titlecompound as a white solid (2.2 g, 11.2 mmol, 19%); δH [²H₆]DMSO 8.00(1H,s), 7.34 (1H,d), 7.71 (1H,dd), 4.44 (2H,d), 4.35 (2H,s), 4.28(2H,d), 1.31 (3H,s).

5-(4-Methyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)-2-[tri(n-butyl)stannyl]furan

2-(4-Methyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)furan (2.0 g, 10.2 mmol)was dissolved in THF (20 ml) and the solution was cooled to −78° C.n-Buli (1.6M solution in hexanes, 7.7 ml, 12.32 mmol) was added and themixture stirred at −78° C. for 30 min, allowed to warm to 0° C. for 20min. and then recooled to −78° C. The tributyltin chloride (3.5 ml, 4.68g, 14.4 mmol) was added and stirring was continued at −78° C. for 15min. The mixture was allowed to warm gradually to room temperature andstirring continued for three days. The reaction was quenched by theaddition of water, and extracted with ethyl acetate. This solution waswashed with water, dried (MgSO₄), and concentrated in vacuo to give thetitle compound as a yellow oil (4.7 g, 9.7 mmol, 95%); δH [²H₆]DMSO 6.52(1H,d), 6.38 (1H,d), 3.96 (6H,s), 0.77-1.63 (30H,m).

(1-Bensyl-1H-indazol-5-yl)-(6-[5-(4-methyl-2,6,7-trioxa-bicyclo[2,2,2]oct-1-yl)-furan-2-yl]-pyrido-[3,4-d]pyrimidin-4-yl)-amine

1-Bensyl-1H-indazol-5-yl)-(6-chloro-pyrido-[3,4-d]pyrimidin-4-yl)-amine(0.425 g, 1.10 mmol),5-(4-methyl-2,6,7-trioxa-bicyclo[2,2,2]oct-1-yl)-2-[tri(n-butyl)stannyl]furan(1.95 g, 4.0 mmol) and 1,4-bis(diphenylphosphino)butane palladium (II)chloride (0.068 g, 0.11 mmol) were reacted in dry dioxane (15 ml)according to Procedure B. Purification by silica gel chromatography,eluting with 50-100% ethyl acetate/i-hexane, gave the title compound asa yellow solid (0.451 g, 0.929 mmol, 86%); δH [²H₆]DMSO 10.58 (1H,s),9.14 (1H,s), 8.71 (1H,s), 8.61 (1H,s), 8.16-8.21 (2H,m), 7.68-7.79(2H,m), 7.22-7.36 (5H,m), 7.13 (1H,d), 6.68 (1H,d), 5.69 (2H,s), 4.06(6H,s), 0.86 (3H,s); m/z (M+1⁺)547.

EXAMPLES Example 1

(1-Bensyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-aminehydrochloride

Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and4,6-dichloro-pyrido[3,4-d]pyrimidine; δH [²H₆]DMSO 9.08 (1H,s), 8.92(1H,s), 8.82 (1H,s), 8.23 (1H,d), 8.19 (1H,s), 7.80 (1H,d), 7.70(1H,dd), 7.38-7.22 (5H,m), 5.69 (2H,s); m/z (M+1)⁺387.

Example 2

N4-(1-Bensyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine

Astirred solution of(1-benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(0.5 g) in 33% aqueous dimethylamine (5 ml) was heated at 130° C. in areacti-vial for 17 hr. The cooled mixture was dissolved in chloroform,absorbed onto silica and chromatographed to give the title compound(Procedure C) as a yellow solid; δH [²H₆]DMSO 9.00(1H,s), 8.51(1H,s),8.09(2H,d), 7.55(1H,dd), 7.25(7H,m), 6.39(1H,m), 5.60(2H,s) 3.20 (6H,s);m/z (M+1)⁺396.

Alternatively, 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidineand 5-amino-1 -benzyl-1H-indazole were reacted according to Procedure Ato give the title compound as the hydrochloride salt; δH [²H₆]DMSO11.82(1H,s), 8.95(1H,s), 8.63(1H,s), 8.25(1H,s), 8.15(1H,s), 7.87(1H,d),7.78(1H,s), 7.70(1H,dd), 7.30(5H,m), 5.79(2H,s), 3.23(6H,s); C₂₃H₂₂N₇clrequires C 63.96%, H 5.13%, N 22.70%; found C 63.44%, H 4.99%, N 22.74%.

The hydrochloride salt was partitioned between dichloromethane and 2Nsodium carbonate. Extraction of the aqueous layer with dichloromethanewas followed by drying of the organic phase and concentration in vacuoto give the free base.

Example 3

(1-Benzyl-1H-indazol-5-yl)-6-(N-(2-hydroxyethyl)-N-methylamino)-pyrido[3,4-d]pyrimidin-4-yl)-amine

A stirred solution of(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(0.2 g) in 2-methylaminoethanol (4 ml) was heated at 130° C. in areacti-vial for 96 hr (Procedure C). The cooled mixture was partitionedbetween ethyl acetate and water. The aqueous phases were extracted withethyl acetate. The dried extracts were concentrated in vacuo and theresidue purified by flash chromatography to give the title compound as ayellow solid;δH [²H₆]DMSO/CDCl₃ 9.00(1H,s), 8.85(1H,s), 8.45(1H,s),8.10(2H,d), 7.64(1H,dd), 7.30(7H,m), 7.08(1H,s), 5.60(2H,s), 3.85(4H,m)3.25(3H,s); m/z (M+1)⁺426.

Example 4

(1-Bensyl-1H-indazol-5-yl)-(pyrido[3,4-d]pyrimidin-4-yl)-amine

A stirred solution of(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(0.165 g), 2-(tri-n-butylstannyl)furan (0.139 g) andbis-(triphenylphosphine)palladium (II) chloride (30 mg) in dioxane (10ml) was heated at reflux under nitrogen for 65 hr (Procedure B). Thecooled mixture was absorbed onto silica and chromatographed to give thetitle compound as an orange solid; δH CDCl₃ 9.34(1H,s), 8.82(1H,s),8.70(1H,d), 8.15(1H,d), 8.10(1H,s), 7.65(1H,d), 7.60(1H,s), 7.53(1H,dd),7.40(1H,d), 7.25(6H,m), 5.60(2H,s); m/z (M+1)⁺353.

Example 5

(2-Bensyl-1H-benzimidazol-5yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine

Prepared according to Procedure A from 5-amino-2-bensyl-1H-benzimidazoleand 4,6-dichloro-pyrido[3,4-d]pyrimidine; δH [²H₆]-DMSO 9.13(1H,s),8.93(1H,s), 8.84(1H,s), 8.60(1H,s), 8.05(1H,dd), 7.88(2H,d), 7.50(6H,m), 4.61(2H,s); m/z (M+1)⁺387.

Example 6 N4-(1-Benzyl-1H-indol-5-yl)-N6,N6-dimethyl-pyridol[3,4-pyrimidine-4,6-diamine

The title compound was prepared from(1-benzyl-1H-indol-5-yl)-(6-chloro-pyrido(3,4-d]pyrimidin-4-yl)-amine byan analogous method to Example 2 (Procedure C) as a yellow solid; δHCDCl₃8.98(1H,s), 8.50(1H,s), 7.93(1H,s), 7.30(5H,m), 7.15(2H,m),6.60(1H,d), 6.38(1H,s), 5.35(2H,s), 3.20(6H,s); m/z (M+1)⁺395.

Example 7

N4-(2-Benzyl-1H-benzimidazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]-pyrimidine-4,6-diamine

The title compound was prepared from(2-benzyl-1H-benzimidazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amineby an analogous method to Example 2 (Procedure C) as a yellow solid: δH[²H₆]-DMSO 9.75(1H,s), 8.80(1H,s), 8.32(1H,s), 8.08(1H,bs), 7.50(2H,m),7.30(5H,m), 4.20(2H,s); m/z (M+1)⁺396.

Example 8(1-Benzyl-1-H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-pyrido[3,4-d]-pyrimidin-4-yl)-amine

(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(4.28 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-ylmethyl)-furan (J. ChemSoc., Chem. commun., (1988), p560) (10 g) and1,4-bis(diphenylphosphino)butane palladium (II) chloride (1 g) wereheated at reflux in dioxane (150 ml) for 24 hr (Procedure B). Thesolvent was removed in vacuo and the residue chromatographed on silica.Subsequent trituration gave the title compound as a yellow solid: δH[²H₆]-DMSO 10.46 (1H,s), 9.17 (1H,s), 8.74 (1H,s), 8.52 (1H,s), 8.23(1H,s), 8.18 (1H,s), 7.80-7.68 (2H,m), 7.41-7.22 (5H,m), 7.17 (1H,d),6.80 (1H,d), 6.06 (1H,s), 5.71 (2H,s), 4.20-3.96 (4H,m).

Example 9

5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde

(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolanyl]-furan-2-yl)-pyrido[3,4-d]-pyrimidin-4-yl)-amine(3.03 g) and 2N HCl (50 ml) were stirred in THF (50 ml) for 16 hr. Theresulting precipitate was filtered and washed with water to give thethehydrochloride salt of the product; δH [²H₆]DMSO 11.70 (1H,s), 9.74(1H,s) 9.30 (1H,s), 9.27 (1H,s), 8.85 (1H,s), 8.23 (1H,s), 8.18 (1H,s),7.68-7.87 (3H,m), 7.55 (1H,d), 7.22-7.38 (5H,m), 5.71 (2H,s). Subsequentneutralisation with triethylamine in ethanol/water gave the titlecompound; δH[²H₆]-DMSO 9.64(1H,s), 9.19 (1H,s), 9.09(1H,s), 8.72(1H,s),8.12(2H,m), 7.71(2H,m), 7.63(1H,dd), 7.43(1H,d), 7.20(5H,m), 5.62(2H,s).

Example 10(2S)-1-(5-(4-(1-Benzyl-1H-indazol-5-ylamino)-6-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-ylmethyl)-pyrrolidine-2-carboxylicacid amide hydrochloride

5(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde(800 mg) and L-prolinamide (1.0 g) were mixed in dichloromethane (8 ml)at 25° C. for 1 hr. The solution was cooled to 0° C. and sodiumtriacetoxyborohydride (2.0 g) was added. After 4 hr at 25° C. thereaction mixture was subjected to flash chromatography directly onsilica using 3% methanol in chloroform, to give the free base as yellowsolid; δH [²H₆]DMSO 10.33 (1H,s), 9.13 (1H,s) 8.65 (1H,s), 8.61 (1H,s),8.26 (1H,s), 8.16 (1H,s), 7.75 (2H,m), 7.12-7.33 (7H,m), 7.09 (1H,d),6.56 (1H,d), 5.69 (2H,s), 3.84 (2H,s), 3.31-3.39 (1H, obscured bywater), 3.09-3.14 (2H,m), 1.70-2.20 (4H,m); m/z (M+1⁺) 545. Treatmentwith saturated HCl in ethyl acetate gave the title compound; δH[²H₆]-DMSO 12.25 (1H,s), 9.52(1H,s), 9.27 (1H,s), 8.80 (1H,s),8.53(1H,s), 8.27(1H,s), 8.21(1H,s), 7.83(2H,m), 7.72(1H, s), 7.30(6H,m), 6.93(1H, d), 6.72(2H, s), 4.88(1H, m), 4.60(2H,s), 3.20(2H, s),1.90(4H, m); m/z (M+1)⁺545.

Example 11(1-Benzyl-1H-indazol-5-yl)-(6-(3-methyl-3H-imidazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(0.70 g, 1.81 mmol), 1-methyl-5-[tri(n-butyl)stannyl]imidazole (preparedaccording to the published method: K. Gaare et. al., Acta Chem. Scand.,(1993), 47(1), p57-62) (2.2 g, 6 mmol),1,4-bis(diphenylphosphino)-butane palladium (II) chloride (0.41 g, 0.7mmol) and silver oxide (0.22 g, 1.8 mmol) were reacted in dry dioxaneaccording to Procedure B. Purification by silica gel chromatography,eluting with 10%MeOH/EtOAc, gave the product as a pale brown solid (0.16g, 0.37 mmol, 20%); δH CDCl₃10.62 (1H,s), 9.25 (1H,s), 8.75 (1H,s), 8.60(1H,s), 8.13 (1H,s), 8.03 (1H,s), 7.20-7.78 (9H,m), 5.61 (2H,s), 3.96(3H,s); m/z (M+1⁺) 433.

Example 12 N6,N6-Dimethyl-N4-(1-pyridin-2-ylmethyl-1H-indazol-5-yl)-pyrido[3,4-d]pyrimidine-4,6-diaminehydrochloride

Prepared according to Procedure A from1-(2-Pyridylmethyl)indazol-5-ylamine and4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH[²H₆]DMSO11.75(1H,s), 9.92(1H,s), 8.62(1H,s), 8.55(1H,d), 8.24(1H,s), 8.14(1H,s),7.75(4H,m), 7.33(1H,m), 7.08(1H,d), 5.82(2H,s), 3.20(6H,s); m/z (M+1⁺)397.

Example 13N6,N6-Dimethyl-N4-(1-pyridin-3-ylmethyl-1H-indazol-5-yl)-pyrido[3,4]-pyrimidine-4,6-diaminehydrochloride

Prepared according to Procedure A from1-(3-Pyridylmethyl)-1H-indazol-5-ylamine and4-chlor-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [²H₆]DMSO11.50 (1H,s), 9.90(1H,s), 8.65(1H,d), 8.60(2H,m), 8.25(1H,s),8.14(1H,s), 7.91(1H,d), 7.75 (2H,m), 7.70(1H,s), 7.50(1H,m), 5.80(2H,s),3.20(6H,s); m/z (M+1⁺) 397.

Example 14N4-(1-Benzyl-3-methyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine

Prepared according to Procedure A from1-Benzyl-3-methyl-1H-indazol-5-ylamine and4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [²H₆]DMSO11.75 (1H,s), 8.90(1H,s), 8.62(1H,s), 8.02(1H,s), 7.70(3H,m),7.30(5H,m), 5.62(2H,s), 3.30(6H,s) 2.50(3H,s); m/z (M+1⁺) 410.

Example 15N4-(1-(2-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diaminehydrochloride

Prepared according to Procedure A from1-(2-Fluoro-benzyl)-1H-indazol-5-ylamine and4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [²H₆]DMSO11.45 (1H,s), 8.90(1H,s), 8.63(1H,s), 8.24(1H,s), 8.13(1H,s),7.87(1H,d), 7.70(1H,d), 7.62(1H,s) 7.36(1H,m), 7.20 (3H,m), 5.75 (2H,s),3.22(6H,s); m/z (M⁺) 413.

Example 16N4-(1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diaminehydrochlorideN4-(1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diaminehydrochloride

Prepared according to Procedure A from1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine and4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [²H₆]DMSO11.52 (1H,s), 8.90(1H,s), 8.60(1H,s), 8.24(1H,s), 8.14(1H,s),7.85(2H,m), 7.70(1H,d), 7.49(1H,s) 7.10(3H,m), 5.72(2H,s), 3.19(6H,s);m/z (M+1⁺) 414.

Example 17N4-(1-(4-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diaminehydrochloride

Prepared according to Procedure A from1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine and4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [²H₆]DMSO11.42 (1H,s), 8.90(1H,s), 8.60(1H,s), 8.22(1H,s), 8.14(1H,s),7.86(1H,d), 7.65(1H,d), 7.61(1H,s) 7.32(2H,dd), 7.17(2H,dd), 5.70(2H,s),3.23(6H,s); m/z (M⁺) 414.

Example 18N4-(1-Benzenesulphonyl-1H-indol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diaminehydrochloride

Prepared according to Procedure A from1benzenesulphonyl-1H-indol-5-ylamine and4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [²H₆]DMSO11.64 (1H,s), 8.90(1H,s), 8.60(4H,m), 7.90(1H,d), 7.65(5H,m), 6.92(1H,d)3.20(6H,s); m/z (M⁺) 445.

Example 19N4-(3-Benzenesulphonyl-1-H-indol-5-yl)-N6,N6-dimethyl-pyriko[3,4-d]pyrimidine-4,6-diaminehydrochloride

Prepared according to Procedure A from3-benzenesulphonyl-1-H-indol-6-ylamine and4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [²H₆]DMSO11.55 (1H,s), 11.50(1H,s), 8.90(1H,s), 8.60(1H,d), 8.79(1H,d),8.00(3H,m), 7.86(1H,d) 7.60(5H,s), 3.20(6H,s); m/z (M⁺) 445.

Example 20(1-Benzyl-1H-indazol-5-yl)-(6-imidazol-1-yl-pyrido[3,4]pyrimidin-4-yl)-amine

Imidazole (0.8 g) in dry DMSO was treated with sodium hydride (60%, 0.47g) and(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-aminein a reacti-vial and heated at 120° C. After 7 days, the mixture waspoured onto water and extracted with ethyl acetate. Purification using aBond Elute™ cartridge gave the title compound as a brown solid aftertrituration from water; δH [²H₆]DMSO 10.28 (1H,s), 9.25(1H,s),8.90(1H,s), 8.78(1H,s), 8.67(1H,s), 8.30(1H,s), 8.10(1H,s) 7.88(2H,m),7.40(5H,s), 5.70(2H,s); m/z (M⁺) 419.

Example 21(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,4-triazol-1-yl-pyrido[3,4]pyrimidin-4-yl)-amine

1,2,4-triazole was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4yl)-amineas in Example 20 to give the title compound; δH [²H₆]DMSO 10.53 (1H,s),9.46(1H,s), 9.14(1H,s), 9.01(1H,s), 8.40(1H,s), 8.25(1H,s), 8.15(1H,s)7.75(2H,s), 7.25(5H,m), 5.65(2H,s); m/z (M⁺) 418.

Example 22(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,3-triazol-2-yl-pyrido[3,4]pyrimidin-4-yl)-amine

1,2,3-triazole was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4yl)-amineas in Example 21 to give the title compound; δH [²H₆]DMSO 10.62 (1H,s),9.24(1H,s), 8.73(1H,s), 8.33(1H,s), 8.21(1H,s), 7.80(1H,s), 7.33(5H,m),5.73(2H,s); m/z (M⁺) 420.

Example 23(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,3-triazol-1-yl-pyrido[3,4]pyrimidin-4-yl)-amine

1,2,3-triazole was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4yl)-amineas in Example 21 to give the title compound; δH [²H₆]DMSO 10.53 (1H,s),9.28(1H,s), 9.13(1H,s), 8.89(1H,s), 8.64(1H,s), 8.23(1H,s), 8.10(1H,s),8.00(1H,s), 7.69(2H,s), 7.23(5H,m), 5.62(2H,s); m/z (M⁺) 420.

Example 24(1-Benzyl-1H-indazol-5-yl)-(6-pyrrolidin-1-yl-pyrido[3,4]pyrimidin-4-yl)-amine

Pyrrolidine (2 ml) was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(0.4 g) in a reacti-vial at 100° c. (Procedure C). After 18 hours, thecooled mixture was poured onto water and the precipitate washed with hotether and crystallised from acetone to give the title compound; δH[²H₆]DMSO 10.53 (1H,s), 9.75(1H,s), 8.79(1H,s), 8.30(1H,s), 8.23(1H,s),8.14(1H,s), 7.70(2H,m), 7.28(5H,m), 7.14(1H,s), 5.68(2H,s), 3.50(4H,m),2.02(4H,m); m/z (M⁺) 422.

Example 25(1-Benzyl-1H-indazol-5-yl)-(6-piperidin-1-yl)-pyrido[3,4]pyrimidin-4-yl)-amine

Piperidine was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amineas in Example 24 to give the title compound (Procedure C); δH [²H₆]DMSO9.80 (1H,m), 8.80(1H,s), 8.33(1H,s), 8.22(1H,s), 8.15(1H,s), 7.70(2H,m),7.50(1H,s), 7.28(5H,m), 5.68(2H,s), 3.65(4H,m), 1.65(6H,m); m/z (M⁺)436.

Example 26N4-(1-Benzyl-1H-indazol-5-yl)-(6-piperidin-1-yl)-pyrido[3,4]pyrimidin-4,6-diamine

Ethylmethylamine was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amineas in Example 2 to give the title compound (Procedre C); δH [²H₆]DMSO9.87 (1H,s), 8.86(1H,s), 8.37(1H,s), 8.25(1H,s), 8.20(1H,s), 7.76(2H,m),7.35(5H,m), 5.75(2H,s), 3.79(2H,q), 3.18(3H,s), 1.19(3H,t); m/z (M⁺)410.

Example 272-(4-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-piperazin-1-yl)-N-isopropyl-acetamide

4-Isopropylacetamido-1,4-piperazine (Aldrich) was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amineas in Example 24 to give the title compound (Procedure C); δH [²H₆]DMSO8.35(1H,s), 8.20(1H,d), 7.72(2H,m), 7.55(1H,s), 7.30(5H,m),5.70(2H,s)3.95(1H,m), 3.68(4H,bs), 3.00(2H,s), 2.60(4H,bs), 1.10(5H,d); m/z (M⁺)535.

Example 282-(4-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-piperazin-1-yl)-1-morpholin-4-yl-ethanone

N-Morpholinylacetamido-1,4-piperazine (Emkachem) was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amineas in Example 24 to give the title compound (Procedure C); δH [²H₆]DMSO9.80(1H,s), 8.83(1H,s), 8.38(1H,s), 8.22(1H,s), 8.15(1H,s),7.75(1H,d)7.66(1H,dd),7.55(1H,s), 7.28(5H,m), 5.70(2H,s), 3.60(10H,m), 3.50(2H,m),3.28(3H,s), 2.62(4H,bs); m/z (M⁺) 564.

Example 29(1-Benzyl-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-aminehydrochloride

4-Chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl) pyrido[3,4-d]pyrimidine (0.02g) was reacted with 1-benzylindazol-5-ylamine according to Procedure Ato give the title compound as a yellow solid; δH [²H₆]DMSO 11.50(1H,s),9.55(1H,s), 9.43(1H,s), 8.95(1H,s), 8.34(2H,m),7.91(1H,d)7.83(1H,dd),7.40(5H,m), 5.80(2H,s), 2.75 (3H,s); m/z (M+1⁺) 435.

Example 30(1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-aminehydrochloride

Prepared according to Procedure A from1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine and4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidine; δH[²H₆]DMSO 11.50(1H,s), 9.53(1H,s), 9.41(1H,s), 8.94(1H,s), 8.30(2H,s),7.90(1H,d), 7.80(1H,dd), 7.45(1H,d),7.25(3H,m) 5.80(2H,s), 2.75 (3H,s);m/z (M+1⁺) 453.

Example 31(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-aminehydrochloride

Prepared according to Procedure A from 1-benzyl-1H-indol-5-ylamine and4,6-dichloro-pyrido[3,4-d]pyrimidine; δH [²H₆]DMSO 11.45(1H,s),9.08(1H,s), 8.95(1H,s), 8.80(1H,s), 7.98(1H,d), 7.60(2H,m), 7.30(6H,m),6.60(1H,d), 5.48(2H,s); m/z (M+1⁺) 386.

Example 32(1-Benzyl-1H-indazol-5-yl)-(6-(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

4-Methylpiperazine was reacted with(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amineas in Example 24 to give the title compound (Procedure C); δH [²H₆]DMSO9.80(1H,s), 8.82(1H,s), 8.47(1H,s), 8.23(1H,s), 8.15(1H,s), 7.75(1H,d),7.67(1H,d), 7.54(1H,s), 7.28(5H,m), 5.68(2H,s) 3.64(4H,m), 3.34(4H,m),2.27(3H,s); m/z (M⁺) 451.

Example 33(1-Benzyl-1H-indazol-5-yl)-(6-benzyloxy-pyrido[3,4-d]pyrimidin-4-yl)-aminehydrochloride

6-Benzyloxy-4-chloro-pyrido[3,4-d]pyrimidine (0.54 g, ca. 2 mmol) and5-amino-1-benzyl-1H-indazole (0.458 g, 2.05 mmol) were reacted accordingto Procedure A to give the title compound as a yellow solid (0.740 g,1.50 mmol, 75%); δH [²H₆]DMSO 11.50(1H,s), 9.00(1H,s), 8.77(1H,s),8.16-8.33 (3H,m), 7.83(1H,d), 7.71 (1H,dd), 7.13-7.58 (10H,m),5.69(2H,s), 5.55(2H,s); m/z (M+1⁺) 459.

Example 34(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesuphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido-[3,4-d]pyrimidin-4-yl)-aminehydrochloride

5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde(0.70 g, 1.81 mmol), 2-(methanesulphonyl)ethylamine hydrochloride (1.30g, 8.14 mmol) and triethylamine (0.65 ml,0.47 g, 4.7 mmol) were stirredin dichloromethane (7 ml) at room temperature for 1 hour forming aprecipitate. The mixture was cooled to 0° c. and sodiumtriacetoxyborohydride (1.60 g, 7.5 mmol) was added. The temperature wasmaintained at 0° C. for 15 min and then stirring was continued at roomtemperature overnight. The reaction mixture was diluted with water, andthe resulting pale yellow preciptate was collected and washed with waterand acetone. This was resuspended in a mixture of acetone and methanoland acidified with ethereal HCl. The solvents were removed in vacuo andthe residue suspended in acetone and collected by filtration. This wasdried at 60° c. in vacuo to give the product as an orange-yellow solid(0.40 g, 0.64 mmol, 35%); δH [²H₆]DMSO 11.40(1H,s), 9.88(1H,br s),9.52(1H,s), 9.22 (1H,s), 8.80 (1H,s), 8.31 (1H,s), 8.19 (1H,s),7.77-7.90 (2H,m), 7.21-7.37 (6H,m), 6.98 (1H,d), 5.70 (2H,s), 4.47(2H,d), 3.42-3.80 (4H,m, obscured by water), 3.14 (3H,s); m/z (M+1⁺)554.

Example 35(5[4(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl)-furan-2-carboxylicacid hydrochloride

(1-Benzylindazol-5-yl)-(6-(5-(4-methyl-2,6,7-trioxa-bicyclo[2,2,2]oct-1-yl)-furan-2-yl]-pyrido-[3,4-d]pyrimidin-4-yl)-amine(0.445 g, 0.81 mmol) was suspended in a mixture of THF (15 ml) anddilute HCl (15 ml) and stirred at room temperature for 18 hours. Themixture was diluted with water to preciptate the intermediate (partialhydrolysis) which was collected by filtration and washed with water.This solid was suspended in a mixture of THF (10 ml) and NaOH (1M, 10ml) and stirred at room tmperature for 18 hours. The THF was removed invacuo and the residue was acidified to pH1 with dilute HCl to give theproduct as an orange solid, which was collected by filtration (0.322 g,0.645 mmol, 79%); δH [²H₆]DMSO 10.63(1H,s), 9.19(1H,s), 8.89(1H,s), 8.64(1H,s), 8.17-8.22 (2H,m), 7.67-7.80 (2H,m), 7.46 (1H,s), 7.23-7.39(6H,m), 5.70 (2H,s); m/z (M+1⁺) 463.

Example 36(5[4(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylicacid 2-methanesulphonyl-ethylamide hydrochloride

5-[4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylicacid hydrochloride (0.125 g, 0.25 mmol) and carbonyl diimidazole (0.052g, 0.33 mmol) were suspended in dry THF (3 ml) under a nitrogenatmosphere and stirred at room temperature for 7 hours.2-(Methanesulphonyl)ethylamine hydrochloride (0.080 g, 0.50 mmol) andtriethylamine (0.15 ml, 0.11 g, 1.08 mmol) were added, together withfurther THF (2 ml), and the resulting mixture was stirred at roomtemperature for 18 hours. The mixture was absorbed onto silica gel andpurified by column chromatography, eluting with 2-10% MeOH/DCM.Concentration of the relevant fractions gave a pale yellow solid. Thiswas resuspended in methanol and treated with ethanolic HCl to give theproduct as an orange solid, which was collected by filtration, washedwith methanol, acetone and ether, and dried in vacuo (0.093 g, 0.154mmol, 61%); δH [²H₆]DMSO 12.00(1H,s), 9.76(1H,s), 9.19-9.29 (2H,m), 8.75(1H,s), 8.28 (1H,s), 8.22 (1H,s), 7.78-7.90 (2H,m), 7.23-7.38 (7H,m),5.71 (2H,s), 3.50-3.90 (2H obscured by water signal), 3.48 (2H,t), 3.07(3H,s); m/z (M+1⁺) 568.

Examples 37 and 38N4-(1-Benzyl-1H-indazol-5-yl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine;

N4-[1-(4-Hydroxybenzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine

Prepared by incubation ofN4-(1-Benzyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diaminewith Streptomyces rimosus subsp. paromomycinus (NRRL 2455). Themicro-organism was stored frozen (−80° C.) on porous beads in cryovialscontaining cryopreservative (Microbank™ beads, Richmond Hill, Ontario,Canada). A single bead was used to inoculate each of 2×50 ml aliquots ofculture medium (SB1) dispensed in 250 ml Erlenmeyer flasks.

The microorganism was grown in SB1 medium at a temperature of 28° C.Flasks were shaken at 250 rpm. The SB1 culture medium consisted ofArkasoy (25 g; British Arcady Company), Bacto yeast extract (5 g; DifcoLaboratories) and KH₂PO₄ (5 g) in distilled water (900 ml). The pH ofthe culture medium was adjusted to 7.2 using conc. NaOH prior toautoclaving (15 min./121° C.) 100 ml of a 20% (w/v) solution of glucose(filter sterilised) was added post sterilisation.

N4-(1-Benzyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine(12.5 mg) in methanol (1.0 ml) was added to each culture flask after 72hours growth. Cultures were harvested 7 days after compound addition.

Isolation: The culture broth (2×50 ml) was mixed with an equal volume ofmethanol (containing 0.6% (v/v) TFA), centrifuged (4000 rpm, 4C, 30 min)and the supernatant concentrated under a stream of nitrogen gas. Theresulting concentrated aqueous extract was adsorbed onto awater-equilibrated C18 SPE cartridge (2 g; Varian Ltd., Walton-onThames, UK) which was washed with water (5 volumes), then eluted with3×5 ml methanol (containing 0.3% (v/v) TFA). The eluent was then diluted(mobile phase A, 10 ml) and filtered (0.2 mm PTFE filter) prior topreparative HPLC using the following system: —Spherisobr SB5 C6 15 cm×20mm, flow rate 20 ml/min, detection wavelength 232 nm; mobile phase A: 50mM ammonium acetate containing 3 ml/l TFA; mobile phase B: 50%acetonitrile, 50 mM ammonium acetate containing 3 ml/l TFA; gradient: 0to 30 min, 100%A—100%B; 30 to 35 min, 100%B; 35 to 37 min, 100%B—100%A;37 to 40 min, 100%A. Appropriate fractions were absorbed ontowater-equilibrated C18 SPE cartridges (200 mg; Varian Ltd.,Walton-on-Thames, UK), which were washed with water (5 volumes) theneluted with 2×1 ml methanol (containing 0.3% (v/v) TFA). The solvent wasremoved in vacuo to yield the title compounds.

From the incubation was obtained:

N4-(1-Benzyl-1H-indazol-5-yl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine(0.9 mg); δH [²H₆]DMSP 10.95(1H,s), 8.79(1H,s), 8.63 (1H,s), 8.21(1H,s), 8.15 (1H,s), 7.82 (1H,d), 7.67 (1H,d), 7.20-7.38 (6H,m), 5.71(2H,s), 2.91 (3H,s); andN4[1-(4-Hydroxybenzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine(1.5 mg); δH[²H₆]DMSO 11.30 (1H,s), 9.55 (1H,br s), 8.89 (1H,s), 8.73(1H,s), 8.20 (1H,s), 8.09 (1H,s), 7.84 (1H,d), 7.64 (1H,d), 7.50 (1H,s),7.17 (2H,d), 6.71 (2H,d), 5.58 (2H,s), 3.20 (6H,s).

Examples 39 to 41

The following compounds (and their hydrochlorides, if appropriate) areprepared by analogous techniques using the approprite startingmaterials:

N4-[1-(S,R-α-Methylbenzyl)-1H-indazol-5-6l]-N6,N6-dimethyl-pyrido-[3,4-d]pyrimidin-4,6-diamine;

N4-(3Benzylsulphonyl-1H-indazol-6-yl)-N6,N6-dimethyl-pyrido[3,4-d]-pyrimidine-4,6-diamine;

N4-(3-Benzyl-1H-indazol-6-yl)-N6,N6-dimethyl-pyrido[3,4-d]-pyrimidine-4,6-diamine.

Biological Data

Compounds of the present invention were tested for protein tyrosinekinase inhibitory activity in substrate phosphorylation assays and cellproliferation assays.

The substrate phosphorylation assays use baculovirus expressed,recombinant constructs of the intracellular domains of c-erbB-2 andc-erbB-4 that are constitutively active and EGFr isolated fromsolubillised A431 cell membranes. The method measures the ability of theisolated enzymes to catalyse the transfer of the γ-phosphate from ATPonto tyrosine residues in a biotinylated synthetic peptide(Biotin-GluGluGluGlu TyrPheGluLeuVal). The enzyme is incubated for 30minutes, at room temperature, with 10 mM MnCl₂, ATP and peptide at Kmconcentrations, and test compound (diluted from a 5 mM stock in DMSO,final DMSO concentration is 2%) in 40 mM HEPES buffer, pH 7.4. Thereaction is stopped by the addition of EDTA (final concentration 0.15mM) and a sample is transferred to a streptavidin-coated 96-well plate.The plate is washed and level of phosphotyrosin on the peptide isdetermined using a Europium-labelled antiphosphotyrosine anitbody andquantified with a time-resolved fluorescence technique. The results areshown in Table 1 as the IC₅₀ values in nM.

The cell proliferation assay uses an immortalised human breastepithelial cell line (HB4a) which has been transformed byover-expression of c-erbB-2. Growth of these cells in low serum isdependent upon the c-erbB-2 tyrosine kinase activity. The specificity ofthe effect of the test compounds on tyrosine kinase dependent growthover general toxicity is assessed by comparison to an HB4a cell linewhich has been transfected with ras. Cells are plated at 3000/well in96-well plates in 0.1 ml medium and allowed to attach overnight. testcompound is added in 0.1 ml medium, with a final concentration of 0.5%DMSO, and the plates incubated for 4 days at 37° C. The cells are thenexamined microscopically for evidence of morphological detransformationand cell mass is estimated by staining with methylene blue and measuringthe absorbance at 620 nm. The results are shown in Table 1 below as theIC₅₀ values in nM. Activity against a range of naturally occurring EGFror c-erbB-2 over-expressing human tumour cell lines (BT474-breast,HN5-head and neck, N87-gastric and Calu3-lung) is assessed with selectedcompounds by the same methodology. The results are also shown in Table 1below as the IC₅₀ values in nM.

TABLE 1 Cell Proliferation Exam- Substrate Phosphorylation HB4a ple EGFrerbB-2 erbB-4 erbB-2 HB4a ras BT474 N87 Calu3 HN5 1 27 48 2 1 19 20 11017000 140 240 380 300 3 7 23 140 33000 1800 4 120 1300 3900 13000 6 11150 320 7 7 21 1900 19000 610 8000 10 6 10 71 21000 2 2 160 130 11 15 955 1400 3800 1400 370 1200 1400 12 77 1 3 170 32000 13 370 50 2400 24028000 14 830 430 1500 950 7900 15 7 4 4 14000 16 9 96 44 11000 1 120 18081 17 250 490 7600 550 7000 18 290 98 1700 21 19000 440 19 540 6 1301200 33000 20 4 33 470 14000 21 54 500 18000 22 22 1700 18000 23 31 25022000 24 20 140 810 50000 460 900 25 380 60 570 480 >50000 270 940 26 5429 150 8900 27 2 190 380 21000 28 4 170 590 28000 29 2 2 5500 5200 2900011000 10000 30 2 2 9600 2900 26000 32 55 140 100 8800 1000 600 8200 420033 1900 140 2700 >50000 50000 34 15 230 70 17000 2 190 1300 190 35 160027000 >50000 36 1600 3100 >50000 37 30 65 180 520 17000 1100 2200 37002000 38 930 330 1900 6900 50000

What is claimed is:
 1. A compound of formula (I):

or a salt or solvate thereof; wherein X is N; Y is a group W(CH₂),(CH₂)W, or W, in which W is 0, S(O)_(m) wherein m is 0, 1 or 2, orNR^(a) wherein R^(a) is hydrogen or a C₁₋₈alkyl group; either n is 1, pis 0 and R″ is selected from the group consisting of phenyl, furan,thiophene, pyridine, pyrimidine, pyrazine, pyrrole, oxazole, isoxazole,oxadiazole, thiazole, isothiazole, triazole, tetrazole, and imidazole ora hydrogenated derivative thereof, said group being optionallysubstituted by one or more R¹ groups; wherein R¹ is either selected fromM¹-M²-M³-M⁴, M¹-M⁵ or M¹-M²-M^(3′)-M⁶, or j selected from the groupconsisting of amino, hydrogen, halogen, hydroxy, hydroxy-C₁₋₄alkyl,formyl, carboxy, cyano, nitro, C₁₋₈alky, C₁₋₈alkoxy, C₁₋₈alkylthio,C₁₋₈alkylsulphinyl, C₁₋₈alkylsulphonyl, C₁₋₄alkylamino,C₁₋₄dialkylamino, dioxolanyl, or hydroxy-C₁₋₄alkanoyl-(C₁₋₄alkyl)-amino;or n is 0, p is 0, 2, or 3 and each R¹ is selected from the groupconsisting of amino, hydrogen, halogen, hydroxy, hydroxy-C₁₋₄alkyl,formyl, carboxy, cyano, nitro, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkylthio,C₁₋₈alkylsulphinyl, C₁₋₈alkylsulphonyl, C₁₋₄alkylamino,C₁₋₄dialkylamino, dioxolanyl, benzyloxy, or hydroxy-C₁₋₄alkanoyl-amino;or when p is 2 or 3, two adjacent R¹ groups together form an optionallysubstituted methylenedioxy or ethylenedioxy group; or n is 0, p is 1 andR¹ is selected from M¹-M²-M³-M⁴, M¹-M⁵ or M¹-M²-M^(3′)-M⁶; or selectedfrom the group consisting of amino, hydrogen, halogen, hydroxy,hydroxy-C₁₋₄alkyl, formyl, carboxy, cyano, nitro, C₁₋₈alkyl,C₁₋₈alkylthio, C₁₋₈alkylsulphinyl, C₁₋₈alkylsulphonyl, C₁₋₄alkylamino,C₁₋₄dialkylamino, dioxolanyl, benzyloxy, orhydroxy-C₁₋₄alkanoyl-(C₁₋₄alkyl)-amino; M¹ represents a C₁₋₄alkyl group,wherein optionally a CH₂group is replaced by a CO group; M² represents aNR¹² or CR¹²R¹³, in which R¹² and R¹³ each independently represent H orC₁₋₄alkyl; M³ represents a C₁₋₄alkyl group; M^(3′) represents aC₁₋₄alkyl group or is absent; M⁴represents CN, NR¹²S(O)_(m)R¹³,S(O)_(m)NR¹⁴R¹⁵, CONR¹⁴R¹⁵, S(O)_(m)R¹³ or CO₂R¹³, in which R¹², R¹³ andm are as hereinbefore defined and R¹⁴ and R¹⁵ each independentlyrepresent H or C₁₋₄alkyl, or R¹⁴ and R¹⁵ together with the nitrogen atomto which they are attached represent a 5- or 6-membered ring optionallycontaining 1 or 2 additional heteroatoms selected from N, O or S(O)_(m)in which ring any nitrogen atom present may optionally be substitutedwith a C₁₋₄alkyl group; M⁵ represents the group NR¹⁴R¹⁵ or the group

and M⁶ represents a C₃₋₆ cycloalkyl group, the group NR¹⁴R¹⁵ or a 5- or6-membered heterocyclic ring system containing 1 to 4 heteroatomsselected from N, O or S; R² represents hydrogen; U represents anindolyl, isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl,2,3-dihydro-1H-indazoylyl, 1H-benzimidazoylyl,2,3-dihydro-1H-benimidazoylyl or 1H-benzotriazoylyl group which issubstituted by at least one independently selected R⁶ group and isoptionally substituted by at least one independently selected R⁴ group,each R⁴ is independently hydrogen, hydroxy, halogen, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄alkylamino, di-amino, C₁₋₄alkylthio, C₁₋₄alkylsulphinyl,C₁₋₄alkylsulphonyl, C₁₋₄alkylcarbonyl, C₁₋₄alkylcarbamoyl, di-carbamoyl,carbamyl, C₁₋₄alkoxycarbonyl, cyano, nitro or trifluoromethyl; each R⁶is independently benzyl, halo-, dihalo- and trihalobenzyl,α-methylbenzyl, phenyl, halo-, dihalo-, and trihalophenyl, pyridyl,pyridylmethyl, pyridyloxy, pyridylmethoxy, thienylmethoxy,dioxolanylmethoxy, cyclohexylmethoxy, phenoxy, halo-dihalo-, andtrihalophenoxy, phenylthio, benzyloxy, halo-, dihalo-, trihalobenzyloxy,C₁₋₄alkoxybenzoyloxy, phenyloxalyl or benzenesulphonyl; and A represents


2. A compound as claimed in claim 1 wherein Y is NR^(a), NR^(a)(CH₂), or(CH₂)NR^(a).
 3. A compound as claimed in claim 1 wherein n is 0 and eachR¹ is selected from the group comprising amino, C₁₋₄alkylamino,di-C₁₋₄alkylamino.
 4. A compound as claimed in claim 1 wherein n is 0, pis 1 and R¹ is selected from the group comprising amino, C₁₋₄alkylamino,diC₁₋₄alkylamino.
 5. A compound as claimed in claim 1 wherein M¹represents CH₂, CO, CH₂CH₂ or CH₂CO; M² represents NR¹² in which R¹² isas defined in claim 1; M³ represents CH₂, CH₂CH₂ or propyl; M^(3′)represents CH₂, ethyl, propyl, isopropyl or is absent; M⁴ representsSOR¹³, SO₂R¹³, NR¹²SO₂R¹³ or CONR¹⁴R¹⁵ in which R¹² and R¹³ are definedin claim 1 and R¹⁴ and R¹⁵ each independently represent H or C₁₋₄alkyl;M⁵ represents a group NR¹⁴R¹⁵ in which R¹⁴ and R¹⁵ together with thenitrogen atom to which they are attached represents a 6-membered ringoptionally containing an additional heteroatom selected from N or O,wherein said heteroatom may optionally be substituted with a C₁₋₄alkylgroup when it represents N; or M⁵ represents a group

in which t represents 2 or 3 and R¹⁶ represents OH, NH₂, N(C₁₋₄alkyl)₂or OC₁₋₄alkyl; or M⁵ represents a group NR¹⁴R¹⁵ in which R¹⁴ and R¹⁵each independently represent hydrogen or C₁₋₄alkyl; and M⁶ represents agroup NR¹⁴R¹⁵ in which R¹⁴ and R¹⁵ each independently representC₁₋₄alkyl; or R¹⁴ and R¹⁵ together with the nitrogen atom to which theyare attached represent a 5- or 6-membered ring optionally containing anadditional heteroatom selected from N or O, wherein any N atom presentin the 5- or 6-membered ring may optionally be substituted with aC₁₋₄alkyl group; or M⁶ represents a 5- or 6-membered heterocyclic ringsystem containing 1 or 2 heteroatoms selected from N or O.
 6. A compoundas claimed in claim 1 wherein M²-M³-M⁴ together represents an α-aminocarboxylic acid or a methyl ester or amide thereof; or M²-M³-M⁴represents a β-or γ-amino sulphinic or sulphonic acid or a methyl estertherof.
 7. A compound as claimed in claim 1 wherein M²-M³-M⁴ togetherrepresents a methylsulphonylethylamino, methylsulphinylethylamino,methylsulphonylpropylamino, methylsulphinylpropylamino,methylsulphonamidoethylamino, sarcosinamide, glycine, glycinamide, orglycine methyl ester group.
 8. A compound as claimed in claim 1 whereinM¹-M⁵ together represents a piperaziinyl-methyl,methylpiperazinyl-methyl, piperidinyl-methyl, prolinamidomethyl,N,N-dimethylprolinamido-methyl, isopropylacetamido orN-morpholinoacetamido group.
 9. A compound as claimed in claim 1 whereinR″ is selected from the group comprising phenyl, furan, imidazole,tetrazole, pyrrolidine, piperazine, piperidine and oxadiazole.
 10. Acompound as claimed in claim 1 wherein R⁶ is benzyl, fluorobenzyl,benzyloxy, fluorobenzyloxy, pyridylmethyl, phenyl, benzenesulphonyl,phenoxy or fluorophenoxy.
 11. A compound as claimed in claim 1 wherein Arepresents a pyridine ring; and either (a) p is 0; n is 1; and the groupR″ is in the 6-position of the pyridopyrimidine ring system or (b) n is0; p is 1; and the group R¹ is in the 6-position of the pyridopyrimidinering system.
 12. A compound of forumula (I) or a salt or solvate thereofas claimed in claim 1 wherein X represents N; Y represents NR^(a),wherein R^(a) is hydrogen or C₁₋₄alkyl; A represents a pyridine ring; R″is as defined in claim 1 optionally substituted by one or more R¹ groupsselected from halo, C₁₋₄alkyl, cqrboxy, formyl, hydroxy-C₁₋₄alkyl,1,3-dioxolan-2-yl, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,hydroxy-C₁₋₄alkanoyl(C₁₋₄alkyl)amino, C₁₋₄alkylamino-C₁₋₄alkyl ordi(C₁₋₄alkyl)amino-C₁₋₄alkyl; p is 0; R² represents hydrogen; R⁴represents hydrogen or methyl; U represents indolyl, benzimidazolyl orindazolyl; and R⁶ represents phenyl, benzyl, α-methylbenzyl,fluorobenzyl, benzenesulphonyl, phenoxy, fluorophenoxy, benzyloxy orfluorobenzyloxy.
 13. A compound of formula (I) or a salt or solvatethereof as claimed in claim 1 wherein Y represents NR^(a), wherein R^(a)is hydrogen or C₁₋₄alkyl; A represents a pyridine ring, R″ is as definedin claim 1 optionally substituted with an R¹ group selected frommethylsulphonylethylaminomethyl, methylsulphonylethylamino-carbonyl,methylsulphinylethylamino-methyl, methylsulphinylethylamino-carbonyl,methylsulphonylpropylamino-methyl, methylsulphinylpropylamino-methyl,methylsulphonylpropyamino-carbonyl methylsulphinylethylamino-carbonyl,methylsulphonylethyl-(methylamino)-methyl,methylsulphonylethyl-(methylamino)-carbonyl,methylsulphinylethyl-(methylamino)-methyl,methylsulphinylethyl-(methylamino)-carbonyl,methylsulphonylpropyl-(methylamino)-methyl,methylsulphinylpropyl-(methylamino)-methyl,methylsulphonylpropyl-(methylamino)-carbonyl,methylsulphinylpropyl-(methylamino)-carbonyl,methylsulphonamidoethylamino-methyl,methylsulphonamidopropylamino-methyl, sarcosinamidomethyl,glycinylmethyl, glycinamidomethyl, glycinylmethyl methyl ester,acetylaminoethylaminomethyl, piperazinylmethyl, methylpiperazinylmethyl,piperidinylmethyl, N-(proliinamido)methyl,(N,N-dimethyl-prolinamido)methyl, pyridylaminomethyl,cyclopropylaminomethyl, N-(piperidin-4-yl)-N-methylaminomethyl,N,N-dimethylaminoprop-2-ylaminomethyl,N-(2-dimethylaminoethyl)-N-ethylaminomethyl, isopropylacetamido,N-morpholinylacetamido or tetrahydrofuranomethylaminomethyl andoptionally further substituted by one or more C₁₋₄alkyl groups; p is 0;R² represents hydrogen; R⁴ represents hydrogen or methyl; U representsindolyl, benzimidazolyl or indazolyl; and R⁶ represents phenyl, benzyl,α-methylbenzyl, fluorobenzyl, benzenesulphonyl, phenoxy, fluorophenoxy,benzyloxy or fluorobenzyloxy.
 14. A compound of formula (I) or a salt orsolvate thereof as claimed in claim 1 wherein Y represents NR^(a)wherein R^(a) is hydrogen or C₁₋₄alkyl; A presents a pyridine ring; n is0; each R¹ group is selected from hydrogen, halo, C₁₋₄alkyl, carboxy,formyl, hydroxy-C₁₋₄alkyl, 1,3-dioxolan-2-yl, benzyloxy, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,hydroxy-C₁₋₄alkanoyl(C₁₋₄alkyl)amino, C₁₋₄alkylamino-C₁₋₄alkyl,di(C₁₋₄alkyl)amino-C₁₋₄alkyl, methylsulphonylethylaminomethyl,methylsulphonylethylamino-carbonyl, methylsulphinylethylamino-methyl,methylsulphinylethylamino-carbonyl, methylsulphonylpropylamino-methyl,methylsulphinylpropylamino-methyl, methylsulphonylpropylamino-carbonyl,methylsulphinylpropylamino-carbonylmethylsulphonylethyl-(methylamino)-methyl,methylsulphonylethyl-(methylamino)-carbonyl,methylsulphinyletrhyl-(methylamino)-methyl,methylsulphinylethyl-(methylamino)-carbonyl,methylsulphonylpropyl-(methylamino)-methyl,methylsulphinylpropyl-(methylamino)-methyl,methylsulphonylpropyl-(methylamino)-carbonyl,methylsulphinylpropyl-(methylamino)-carbonyl,methylsulphonamidoethylamino-methyl, methyl,methylsulphonamidopropylamino-methyl, sarcosinamidomethyl,glycinylmethyl, glycinamidomethyl, glycinylmethyl methyl ester,acetylaminoethylaminomethyl, piperazinylmethyl, methylpiperazinylmethyl,piperidinylmethyl, N-(prolinamido)methyl,(N,N-dimethyl-prolinamido)methyl, pyridylaminomethyl,cyclopropylaminomethyl, N-(piperidin-4-yl)-N-methylaminomethyl,N,N-dimethylaminoprop-2-ylaminomethyl,N-(2-dimethylaminoethyl)-N-ethylaminomethyl, isopropylacetamido,N-morpholinylacetamido or tetrahydrofuranomethylaminomethyl; R²represents hydrogen; R⁴ represents hydrogen or methyl; U representsindolyl, benzimidazolyl or indazolyl; and R⁶ represents phenyl, benzyl,α-methylbenzyl, fluorobenzyl, benzenesulphonyl, phenoxy, fluorophenoxy,benzyloxy or fluorobenzyloxy.
 15. A compound as claimed in claim 12wherein Y represents NR^(a), wherein R^(a) is hydrogen or C₁₋₄alkyl; Arepresents a pyridine ring; R″ represents a furan, imidazole, triazole,oxadiazole, pyrrolidine, piperidine or piperazine ring, optionallysubstituted by one or more R¹ groups selected from 1,3-dioxolan-2-yl,formyl, carboxy, C₁₋₄alkyl, prolinamidomethyl, isopropylacetamido,N-morpholinylacetamido, methylsulphonylethylaminomethyl ormethylsulphonylethylaminocarbonyl; p is 0; R² represents hydrogen; R⁴represents hydrogen or methyl; U represents indazolyl, indolyl orbenzimidazolyl; and R⁶ represents benzyl, fluorobenzyl, pyridylmethyl orbenzenesulphonyl.
 16. A compound as claimed in claim 15 wherein Yrepresents NR^(a), wherein R^(a) is hydrogen or C₁₋₄alkyl; A representsa pyridine ring; n is 0; each R¹ group is selected from hydrogen, halo,benzyloxy, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino orhydroxy-C₁₋₄alkanoyl-(C₁₋₄alkyl)-amino, more preferably dimethylamino;R² represents hydrogen; R⁴ represents hydrogen or methyl; U representsindazolyl, indolyl or benzimidazolyl; and R⁶ represents benzyl,fluorobenzy, pyridylmethyl or benzenesulphonyl.
 17. A compound asclaimed in claim 1 selected from:(1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4]pyrimidin-4-yl)-amine;N4-(1-Benzyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;(1-Benzyl-1H-indazol-5-yl)-(6(N-(2-hydroxyethyl)-N-methylamino)-pyrido[3,4]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indazol-5-yl)-(pyrido[3,4]pyrimidin-4-yl)-amine;(2-Benzyl-1H-benzimidazol-5-yl)-(6-chloro-pyrido[3,4]pyrimidin-4-yl)-amine;N4-(1-Benzyl-1H-indol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(1-benzimidazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-pyrido[3,4-d]-pyrimidine-4-yl)-amine;5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;2S)-1-(5-(4-(1-Benzyl-1H-indazol-5-ylamino)6-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-ylmethyl)-pyrrolidine-2-carboxylicacid amide;(1Benzyl-1H-indazol-5-yl)-(6-(3-methyl-3H-imidazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;N6,N6-Dimethyl-N4-(1-pyridin-2-ylmethyl-1H-indazol-5-yl)-pyrido[3,4-d]pyrimidine-4,6-diamine;N6,N6-Dimethyl-N4-(1-pyridin-3-ylmethyl-1H-indazol-5-yl)-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(1-Benzyl-3-methyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(1-(2-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(1-(3-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(1-(4-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(1-Benzenesulphonyl-1H-indol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(3-Benzenesulphonyl-1H-indol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;(1-Benzyl-1H-indazol-5-yl)-(6-imidazol-1yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,4-triazol-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,3-triazol-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indazol-5-yl)-(6-(1,2,3-triazol-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indazol-5-yl)-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indazol-5-yl)-(6-piperidin-1-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine;N4-(1-Benzyl-1H-indazol-5-yl)-N6-ethyl-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine;2(4-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-piperazin-1-yl)-N-isopropyl-acetamide;2(4-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-piperazin-1-yl)-N-morpholin-4-yl-ethanone;(1-Benzyl-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1(3-Fluoro-benzyl)-1H-indazol-5-yl)-(6-(5-methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indazol-5-yl)-(6(4-methyl-piperazin-1-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indazolyl-5-yl)-(6-benzyloxy-pyrido[3,4-d]pyrimidin-4-yl)-amine;(1-Benzyl-1H-indazol-5-yl)-(6(5-((2-methanesuphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;5-[4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylicacid;5-[4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido-[3,4-d]pyrimidin-6-yl]-furan-2-carboxylicacid 2-methanesulphonyl-ethylamide;N4-(1-Benzyl-1H-indazol-5-yl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(4-Hydroxyenzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine; and salts or solvatesthereof.
 18. A compound as claimed in claim 17 selected from:N4-(1-Benzyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(3-Fluoro-benzyl)-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine;N4-(1-Benzyl-1H-indazol-5-yl)-N6-ethyol-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine;(1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesuphonyl-ethylamino)-methyl)-furan-2yl)-pyrido[3,4-d]pyrimidine-4-yl-amine;N4-(1-Benzyl-1H-indazol-5-yl)-N6-methyl-pyrido[3,4-d]pyrimidine-4,6-diamine;and salts or solvates thereof.
 19. A pharmaceutical formulationcomprising at least one compound as claimed in claim 1 together with oneor more pharmaceutically acceptable carriers, diluents or excipients.20. A pharmaceutical formulation in unit dosage form containing acompound as claimed in claim 1 in an amount of from 70 to 700 mg.
 21. Amethod of treatment of a human or animal subject suffering from adisorder mediated by aberrant protein tyrosine kinase activity whichcomprises administering to the human or animal subject an effectiveamount of a compound as claimed in claim
 1. 22. A compound of formula(V)

wherein x, R² and A are defined in claim 1; n is 0 and p is 0 to 3; eachR¹ is amino, C₁₋₄alkylamino or di-C₁₋₄alkylamino; and L is a leavinggroup; provided that the following compounds are excluded:4-Chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine;6-Amino-4-chloro-pyrido[3,4-d]pyrimidine.
 23. A compound of formula (V)

wherein X, R² and A are as defined in claim 1; n is 1 and p is 0; and Lis a leaving group.
 24. A compound of formula (VII)

wherein X, R² and A are as defined in claim 1; n is 0 and p is 0 to 3;each R¹ is amino, C₁₋₄alkylamino or di-C₁₋₄alkylamino; provided that thefollowing compounds are excluded:6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidin-4-one;6-Amino-pyrido[3,4-d]pyrimidin-4-one.
 25. A compound of formula (VII)

wherein X, R¹, R², R″ and A are as defined in claim 1; n is 1 and p is0.